Epidemiology, Pathophysiology, and Management of Coronary Artery Disease in the Elderly

Abstract

Elderly patients over the age of ≥ 75 years are especially susceptible to coronary artery disease (CAD) as age is an important nonmodifiable risk factors for atherosclerosis and a predictor of poorer outcomes. In fact, CAD is a major cause of mortality and morbidity in this population. Due to concerns of functional frailty, comorbidities, and patient preference of conservative to no treatment have played a role in reducing the interest in pursuing prospective studies in this high-risk group. In this review, we provide an overview of the epidemiology, pathophysiology, and management of CAD in older adults.

Age is a strong nonmodifiable risk factor for cardiovascular diseases (CVDs) including stroke, myocardial infarction (MI), and peripheral arterial disease. ^{1 2} The prevalence of CVD increases with age, regardless of gender, in both biological men and women. ¹ CVD remains the number one leading cause of mortality in the U.S. Globally, CVD-related deaths were estimated to be nearly 17.6 million (95% confidence interval, 17.3–18.1 million) in 2016, an increase of 14.5% from 2006. ¹ Coronary artery disease (CAD) is a major contributor to the CVD death rate. Another vital factor that accounts for increased mortality is age. The U.S. aged population continues to increase over the last decade and is predicted to grow larger in the next 20 to 30 years. ³ According to the Administration on Aging, the age distribution > 65 years in the United States has changed since 2010 from approximately 13.0 to 17.0% in 2020. ⁴ Furthermore, the age of the U.S. population > 65 years is expected to go up to 22% by 2040 and anticipated to increase as much as two- to threefold by 2050. ⁴ Although age is the strongest risk factor for CAD, many prospective studies eliminate older patients, particularly, those at higher risk. As we continue to advance medically and are capable of developing better, less invasive, tools to diagnose and treat, the advanced aged group with CAD deserves more medical care and attention. Age > 75 years is often cited as the beginning of old age and > 85 years is often used to designate very old age. ⁵ Data suggests that by 75 and 85 years, respectively, most adults have incurred sufficient aging vascular changes resulting in differences in physiology and organ function and reserve. ⁵ This article reviews our understanding of CAD risk factors, epidemiology, pathophysiology, medical management strategies, and outcomes of this aged population above ≥ 75 years of age.

Pathophysiology

Autopsy studies to evaluate the lesion formation of CAD have shown that over 60% are the result of obstructive plaque formation. ⁶ This may cause fatal thrombosis in the acute manifestation of CAD. ⁷ Intraplaque hemorrhage, superficial erosion, and calcified nodules are other mechanisms that contribute to lethal thrombotic events. ^{7 8}

Biological CAD risk factors are multifactorial and may lead to ischemic disease due to atherosclerosis, or thrombotic events. Disruption to homeostasis in advanced age via increased endothelial dysfunction, platelet coagulation/fibrinolytic cascade, and vessel inflammation may further enhance the thrombotic risk. ⁹ Several studies have demonstrated vascular remodeling with aging through endothelial dysfunction or arterial stiffness. Reduction of nitric oxide (NO) with aging plays a key factor in the dysregulation of vasodilatory and antithrombotic mechanisms. ⁶ This process is mediated by alteration in precursor endothelial NO synthase (eNOS), with a mechanism called eNOS uncoupling. ¹⁰ This in return leads to a decline in NO release by decreasing synthesis or increasing degradation. Tetrahydrobiopterin (BH4), a cofactor in NO production, in older mice is thought to decline as a result of impaired guanosine-5′-triphosphate synthesis. ¹¹ Additionally, low BH4 escalates the progression of reactive oxygen species, mediating more inflammation and further depletion of NO. Other inflammatory markers such as tumor necrosis factor-a, and nicotinamide adenine dinucleotide phosphate, nicotinamide adenine dinucleotide protein known as sirtuins can also impede the NO synthesis process. ^{7 11 12}

The renin-angiotensin-aldosterone system (RAAS) produces cytokines associated with advanced age, which increase NO inactivation. ¹³ Vasoconstrictors including cyclooxygenase, prostaglandins, and thromboxane change substantially with older age causing significant endothelial injury. ⁶ Besides vasodilatory dysfunction, increased stiffness is another vascular change associated with aging. Structurally, loss of elastin and increased collagen reduces vascular elasticity. Similar to vasoconstriction, certain inflammatory markers, RAAS, and enzymatic degradation process augment collagen accumulation and arterial inelasticity. ¹⁴ Stiff arteries predispose the vasculature to endothelial damage, inflammation, and thrombosis. ¹⁵ Epigenetic studies in older patients are being pursued to identify cardiovascular aging changes and associated inflammatory and remodeling markers. Many traditional risk factors that have been linked to CAD are also accentuated in the advanced age population.

Epidemiology

While older adults only account for 6% of the global population, they represent majority of those with CVD. ¹⁶ Age is the strongest nonmodifiable risk factor for CAD and all types of increased CVDs in older adults. ³ According to the American Heart Association (AHA) 2019 update, 31% of male and 25.4% female patients ≥ 80 years of age have CAD. ¹⁷

Risk Factors

Atherosclerosis is the result of compounded accumulation of risk factors and aging processes. Key common risk factors in the progression of CAD include diabetes, hypertension, dyslipidemia, physical inactivity, renal dysfunction, and tobacco use, with conflicting data regarding obesity. Therefore, coronary atherosclerosis in older patients tends to be more extensive than in the younger population but data regarding medical management and guidelines in this age group is lacking.

Hypertension

While hypertension is very common and prevalence increases with age, it is the most modifiable risk factor. According to data analysis from the National Health and Nutrition Examination, older adults > 75 years old have over 75% odds of having hypertension. ¹⁶ Hypertension is often found in > 70% of older adults with stroke, heart failure, aortic syndrome, kidney disease, and incident MI. ¹⁷ Isolated systolic hypertension is very prevalent in the elderly, and an increase of 20/10 mm Hg of blood pressure doubles their cardiovascular risk. In the HYVET (The Hypertension in the Very Elderly Trial) of 3,845 patients > 80 years of age, lowering blood pressure by 15.0/6.1 mm Hg compared with the control group was associated with an average reduction of stroke incidence by 39%, heart failure by 64%, and all-cause mortality by 21%. ¹⁸ Other studies have noted a lowering of MI incidence by 20 to 25%. Several guidelines have set a target for blood pressure to help guide hypertension management in different age groups. The Eighth Joint National Committee (JNC 8) recommends a goal blood pressure < 150/90 in patients > 60 years. ¹⁹ Similarly, the AHA/American College of Cardiology (ACC) guidelines suggest a goal of < 150/80 in patients > 80 years, with some variation in younger groups. ^{20 21}

Diabetes

Diabetes mellitus is common in the elderly and 29% of the U.S. population > 65 years of age has diabetes. ²² Older adults with diabetes are at heightened risk of developing cardiovascular adverse events. ²³ For older patients, the hemoglobin A1C (HbA1C) goal is 7.5 to 8%, as overtreating may cause this population more harm, according to the American Geriatric Society. ²⁴ The American Diabetes Association (ADA) suggests an even higher HbA1C goal of 8 to 8.5%. ²⁵ These recommendations emerged following results of VADT (Veterans Affairs Diabetes Trial), ACCORD (The Action to Control Cardiovascular Risk in Diabetes), and ADVANCE(Action in Diabetes and Vascular Disease-PreterAx and DiamicroN Controlled Evaluation), which found that hypoglycemic events are associated with higher cardiovascular events. ^{26 27 28} However, these randomized control studies lack data representation in patients > 80 years of age. Despite these potential risks, adequate glucose control in elderly improved mortality risk post-MI. Thus, treating elderly patients with metformin as the first line is the recommendation of ADA if glomerular filtration rate (GFR) > 30. ²⁹ Second-line agents such as glucagon-like peptide 1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 (SGLT2) inhibitors have been found to decrease major adverse cardiac events (MACE), all-cause mortality, and hospitalization for heart failure. ^{30 31} Nonetheless, patients > 80 years were not well represented in these clinical trials and future research in the elderly population of second-line diabetic agents is needed. Overall, frail patients with high hypoglycemia risk should have a more lenient A1C.

Dyslipidemia

Dyslipidemia is a major risk factor for CVD and the formation of lipid deposits on the arterial wall is a major component of the atherosclerosis process. ³² Several studies demonstrated high morbidity and death rate among older adults with elevated low-density lipoprotein cholesterol, total cholesterol, and high-density lipoprotein. ³² Besides lifestyle modification, statins remain the first-line treatment in this aged population. ³³ Given limited studies in this advanced age, guidelines for primary prevention in patients > 75 years age are still unclear and heavily based on patient-centered and individualized assessment. The AHA/ACC 2018 guidelines recommends clinician–patient discussion in patient population older than 75 years with diabetes mellitus based on potential risk and benefits for prevention of atherosclerotic CVD (ASCVD) events. ³⁴ Nevertheless, no specific suggestions were made for individuals > 75 years without diabetes and low ASCVD risk.

Limited trials that included individuals > 70 years of age such as EPESE (Established Population for the Epidemiologic Study of the Elderly) and PROSPER (Pravastatin in Elderly Individuals at Risk of Vascular Disease) evaluated patients between the age of 70 and 82 years and noted long-term benefits from statin therapy in lowering CAD events and related mortality. ^{35 36} JUPITER (Justification for the Use of Statin in Prevention: An Intervention Trial Evaluating Rosuvastatin) with a median age of 66 years (males > 50 years and females > 60 years) showed decreased incidence of MACE with the treatment of hyperlipidemia. ³⁷ It has been suggested to use coronary artery calcium score or include robust biomarkers such as N-terminal pro hormone B-type natriuretic peptide, and high-sensitivity C-reactive protein to further assess risk and benefit with use of statin therapy. ³⁸ PREVENTABLE (Pragmatic Evaluation of Events and Benefits of Lipid-Lowering in Older Adults) trial and STAREE (A Clinical Trial of Statin Therapy for Reducing Events in the Elderly) are two large prospective ongoing trials in patients > 70 years old. ^{39 40} These two studies aim to answer this intriguing question of whether to treat older adults for ASCVD primary prevention with pharmacotherapy.

Renal Dysfunction

Chronic kidney disease (CKD) is an independent risk factor for CAD. Individuals with CKD are exposed to uremia-induced CVD risk factors such as oxidative stress, inflammation, and abnormal metabolism of calcium-phosphorus. ⁴¹ There is a linear direct relationship between decline of GFR < 60 mL/min/1.73 m ² , and progression of CAD. ⁴² In comparison with the general population, those with CKD stages 3a to 4 have a two- to threefold elevated risk of death. Older adults have a higher prevalence of CKD, which could happen as an age-related process leading to decline in kidney function or because of other comorbidities including diabetes and hypertension. The CKD population with CKD stage 3a or higher and acute MI (AMI), has a rather unique clinical presentation including dyspnea, and less chest, shoulder, arm, or neck pain. “Oligosymptomatic” non-ST-segment elevation MI (NSTEMI) is more common than ST-segment elevation MI (STEMI) in these patients, and requires high index of suspicion as cardiac troponins are very often elevated in CKD population without acute coronary syndrome (ACS). ⁴³

The use of statin therapy is controversial with limited data to support reduction of MACEs in advanced CKD and dialysis patients. KDIGO (Kidney Disease: Improving Global Outcomes) does not recommend the use of statins in dialysis individuals, but still suggested its use in CKD patients > 50 years old. ⁴² These recommendations were driven from the AURORA (A study to evaluate the Use of Rosuvastatin in subjects On Regular hemodialysis: an Assessment of survival and cardiovascular events) and 4D (Deutsche Diabetes Dialyse Studie) trials. ^{44 45}

Recent trials demonstrated reduction of death, worsening kidney disease, or development of end-stage renal disease (ESRD) with the use of SGLT2 inhibitors, with or without diabetes. ³⁰ Of note, SGLT2 inhibitors are currently one of the most recommended medications in diabetic or heart failure patients to improve cardiovascular risk. Similar to SGLT2 inhibitors, GLP-1RA lead to reduction of traditional cardiovascular risk factors. In addition to improved CAD risk factors such as better glycemic control and weight loss, GLP-1RA has shown to slow the decline of GFR and macroalbuminuria. ^{31 46} Direct benefit of GLP-1RA in diabetic kidney disease is being assessed with the FLOW RCT trial (Semaglutide Works Compared with Placebo in People With Type 2 Diabetes and Chronic Kidney Disease). ⁴⁷

Controversy surrounds revascularization in ACS, except STEMI, in patients with CKD or ESRD as several clinical trials failed to show survival benefits. ⁴⁸ Unfortunately, the number of trials on CAD in CKD patients is very limited, particularly in those with advanced age or CKD stages.

Tobacco Use

Smoking is another modifiable risk factor for CAD. Independent of other risk factors, smoking is associated with advancing cardiovascular mortality in older adults by > 5 years, according to large meta-analysis cohorts from United States, and across Europe in patients > 60 years of age. ⁴⁹ With independent risk for CAD in older adults, smoking cessation becomes essential in reducing additional vascular damage from smoking and CVD prevention in this vulnerable population. ⁵⁰

Management

Although prevalence of CAD is higher among older adults, diagnosis of CAD is quite difficult given the possibility of false elevation of cardiac biomarkers, baseline electrocardiogram changes, and nonspecific clinical presentation.

The treatment approach to CAD in older patients require taking into consideration adverse effects associated with treatment strategy versus potential benefits. For example, advanced age carries with it increased risk for renal impairment, bleeding, thromboembolic events, respiratory failure, and hemorrhagic complications and assessing individualized benefit versus risks of treatment plan is crucial.

Another imperative point is to evaluate cognitive, functionality, and frailty status in this age group because of worse cardiac outcomes following intervention in very frail individuals. ⁵¹ Besides recognizing challenges to invasive intervention in older adults, lifestyle modification, and control of risk factors, prescribing cardiac rehabilitation may provide meaningful cardiovascular benefits. ⁵² Patients > 75 years of age can be exposed to more harm from aspirin use for primary prevention because of increased bleeding risk. Furthermore, alteration of drug metabolism, absorption, clearance, and other pharmacokinetic changes place elderly people at greater risk for side effects. Additionally, drug–drug interaction is very common in this advanced age population because of polypharmacy.

Antithrombotic Therapy

Antiplatelet and anticoagulant drugs are a cornerstone of therapy in older adult patients with CAD, particularly with recurrent ischemic events. According to a meta-analysis from six randomized trials, the use of aspirin for primary prevention did not provide tangible reduction in stroke, MI, or vascular-related mortality. ^{53 54} On the other hand, aspirin is widely accepted and endorsed by current AHA/ACC guidelines for secondary prevention and in ACS irrespective of age. ^{55 56 57 58} Minor bleeding was associated with higher dose aspirin (300 to 325 mg) versus lower dose (75 to 100 mg daily) according to the CURRENT-OASIS 7 (Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events–Seventh Organization to Assess Strategies in Ischemic Syndromes) trial. ^{59 60} Adenosine diphosphate P2Y12 receptor antagonists (P2Y12) such as clopidogrel have been used as an alternative to aspirin in those with aspirin failure or intolerance for secondary vascular prevention. Dual-antiplatelet therapy (DAPT) is the standard treatment in patients who present with ACS. PLATO (Platelet Inhibition and Patient Outcomes) trial showed no superiority of ticagrelor to clopidogrel in older adults > 75 years. Therefore, clopidogrel is the recommended antiplatelet in addition to aspirin in patients > 75 years of age. ⁶¹ However, ticagrelor is a reversible antiplatelet agent, and may be considered as an alternative to clopidogrel. ⁵⁸

Many strategies to reduce bleeding risk are now being considered including shorter DAPT versus single antiplatelet therapy (SAPT) in the elderly. A meta-analysis of individual participant data from six randomized trials of patients aged 65 years or older, did not show significant difference of composite primary endpoint (MI, definite or probable stent thrombosis, or stroke) between short- (3–6 months) and long-term DAPT (12 months) therapy with the use of newer generation drug-eluting stents. ⁶² Also recently, OPT-PEACE (Optimal Antiplatelet Therapy for Prevention of Gastrointestinal Injury) trial showed lower gastrointestinal ulceration with use of SAPT after 6 months of DAPT therapy. ^{63 64 65} This is very promising, yet the study excluded patients > 80 years old, which makes these results not necessarily applicable to older adult population. Overall, individual risk stratification is very vital in mitigating bleeding complications and antithrombotic choice.

Anticoagulant Therapy

Antithrombin therapy including unfractionated heparin (UFH) and low molecular weight heparin (LMWH) are recommended during ACS presentation. Since LMWH are renally cleared, dose adjustment is needed for patients ≥ 75 years of age or those with renal dysfunction. There is no consensus between trials that compared UFH and LMWH regarding safety and efficacy in older adults. ^{53 66 67}

Direct thrombin inhibitors such as bivalirudin were thought to have a safer bleeding profile, but subgroup analysis of the VALIDATE-SWEDEHEART (Bivalirudin versus Heparin in ST-Segment and Non-ST-Segment Elevation Myocardial Infarction in Patients on Modern Antiplatelet Therapy) trial showed no difference in outcomes for patients ≥ 75 years with either heparin or bivalirudin monotherapy. ⁶⁸

The reduced risk of bleeding from factor Xa inhibitors, fondaparinux, made it an attractive selection following the OASIS-5 (Fifth Organization to Assess Strategies in Acute Ischemic Syndromes) trial. There was also no substantial benefit from enoxaparin over fondaparinux in decreasing ischemic events. ^{68 69} However, as with many other trials, no specific outcome in patients ≥ 80 years of age were reported. Moreover, fondaparinux increases catheter thrombosis, primarily excreted by the renal system and contraindicated in advanced renal disease or those undergoing primary percutaneous coronary intervention (PCI). ³⁸

It is common for older adults to have an indication for chronic oral anticoagulation, which becomes very challenging after an MI and concomitant need for antiplatelet agents. Several registry retrospective analyses of older adults showed higher risk of bleeding with triple therapy (DAPT and chronic oral anticoagulation). For example, the GWTG (Acute Coronary Treatment and Intervention Outcomes Network Registry–Get with the Guidelines) demonstrated that triple therapy increases major bleeding risk including intracranial hemorrhage without evidence of improved MACE compared with DAPT alone. ⁷⁰

While definitive guideline on triple therapy in the elderly population is still lacking, results of RE-DUAL PCI (Randomized Evaluation of Dual Antithrombotic Therapy with Dabigatran versus Triple Therapy with Warfarin in Patients with Nonvalvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention), WOEST (What is the Optimal Antiplatelet and Anticoagulant Therapy in Patients with Oral Anticoagulation and Coronary Stenting), and PIONEER AF-PCI (Prevention of Bleeding in Patients with Atrial Fibrillation Undergoing PCI) trials support shorter duration of DAPT or lower dose of anticoagulants in this age group. ^{71 72 73} For example, using low-dose rivaroxaban with DAPT or SAPT was associated with lower risk bleed. Scoring system such as PRECISE-DAPT score has been used to predict risk of bleeding in elderly. According to a multicenter retrospective study, a higher cutoff point of 33, compared with the accepted cutoff of 25 in the younger population, was associated with an augmented risk of bleeding. ^{74 75} This study reported patients ≥ 75 years were susceptible to Bleeding Academic Research Consortium type ≥ 2 if they had PRECISE-DAPT score of 33 or higher. Older patients have an inherently high prevalence of bleeding risk while on antithrombotic treatment for CAD and nonstructural thromboembolic source such as atrial fibrillation. Hence, risk stratification is very crucial to mitigate bleeding complication while minimizing risk for thromboembolic events.

Invasive Therapy

Revascularization remains the primary treatment modality in elderly patients with AMI but remains underutilized. The Treat Angina With Aggrastat and Determine the Cost of Therapy With an Invasive or Conservative Strategy-Thrombolytics in Myocardial Infarction (TACTICS-TIMI)-18 trial showed relatively greater mortality reduction for AMI patients ≥ 75 years of age, based on the efficacy of revascularization and associated adjunctive antithrombotic and DAPT to modify age-related high mortality risk. ⁷⁶ Despite such robust benefits of revascularization, the CRUSADE Quality Improvement Initiative, a community-based registry, showed that 7% of STEMI patients did not undergo revascularization, due to older age. ⁷⁷ Among those with an AMI and who have ST-elevations, primary PCI within 90 minutes remains the standard of care, especially given the increased bleeding risk with thrombolysis for older patients. For elderly with a non-ST elevation AMI, controversy regarding role of invasive management are greater than for STEMI patients and individualized decision making is encouraged taking into account risks versus benefits. Clinicians should factor the mortality benefits of revascularization, but also physical function, frailty, cognition, aggregate morbidity, prognosis, and other comorbidities.

Among stable patients, young adults with SYNTAX (Synergy between PCI with Taxus and Cardiac Surgery) score ≥ 33 had better outcome with coronary artery bypass graft (CABG) in comparison to PCI. ⁷⁸ Compared with PCI, CABG allows more complete revascularization, and the option of combining with valvular surgery for those with severe CAD and concomitant severe valvular heart disease. Furthermore, newer surgical techniques including robotic surgery are associated with reduced morbidity and mortality. ³⁸ PCI is, however, less invasive than CABG, which makes it an attractive option in older adults, particularly those who are frail and at higher risk for neurocognitive deterioration. The choice of treatment should take into consideration patient risk, goal of care, and individual preference.

Cardiac Rehabilitation

CAD management in older adults should include referral for cardiac rehabilitation. Older CAD patients benefit significantly from cardiac rehabilitation with reduced mortality and morbidity, improved quality of life, reduced symptoms, increased functional capacity, and self-sufficiency. Cardiac rehabilitation addresses many associated issues in those with CAD, from the emotional trauma associated with an AMI and/or revascularization to the complexities of polypharmacy, multimorbidity, and frailty, and to the importance of increasing exercise and risk factor modification. Older patients, both frail and robust, benefit from cardiac rehabilitation. The Randomized Evaluation of Secondary Prevention by Outpatient Nurse SpEcialists 2 (RESPONSE-2) trial reported that despite more adverse cardiovascular risk profiles and comorbidities among older patients, nurse-coordinated referral to a community-based lifestyle intervention and rehabilitation was successful in improving risk factors in older patients. ⁷⁹

Conclusion

Elderly patients are at high risk of developing CAD which is a major cause of mortality and morbidity in this population. As in younger populations, therapies in the elderly with CAD include lifestyle modification, appropriate pharmacotherapies, and revascularization but evidence of benefits of such therapies is less robust. While PCI is the preferred therapy for elderly with STEMI, for those with NSTEMI and stable CAD, clinicians should factor benefits versus risks of revascularization, and take into account physical function, frailty, cognition, aggregate morbidity, prognosis, and other comorbidities. Finally cardiac rehabilitation is strongly recommended for the elderly with CAD given robust benefits and minimal risk.