Physical Address
304 North Cardinal St.
Dorchester Center, MA 02124
Cardiovascular Disease in Older Adults
Additional content is available online at Elsevier eBooks for Practicing Clinicians
The population of older adults is expanding throughout the world. In the United States the population age ≥65 years, barely 3 million total in 1900, has climbed to about 46 million and is expected to reach almost 84 million by 2050. The population age ≥85, only about 0.2% of the total in 1900, is anticipated to reach 5% to 6% by 2050. Across the European Union, 20% of the population is over age 65, and more than 29% of Japan’s population is in this age group. Extended lifespan increases exposure to mounting cardiovascular disease (CVD) risk factors and leads to injurious effects that are cumulative over time ; in addition, intrinsic age-related cellular and subcellular physiologic changes increase susceptibility to CVD incidence and progression. Prevalence of almost every type of CVD increases with age, including many conditions that develop predominantly in older adults (e.g., degenerative aortic stenosis [AS], heart failure [HF] with preserved ejection fraction [HFpEF], sick sinus syndrome). Furthermore, CVD in older adults tends to be more complex than in younger populations, both in underlying pathophysiology and because it is more likely to occur in combination with multiple comorbidities. Approximately 70% of adults age ≥65 years in the United States have CVD, including 85% of those age ≥80 years, with disproportionate hospitalizations, procedures, costs, and health care resource utilization. Adults age ≥75 years old comprise only about 6% of the current U.S. population but account for >50% of CVD deaths.
The biologic processes that predispose to CVD in old age also foster higher susceptibility to concomitant diseases and geriatric syndromes. CVDs in older individuals thus occur in a context of comorbidities, frailty, sarcopenia, cognitive decline, and other non-CVDs that add to management complexity. In addition to increased morbidity and mortality, CVD in older adults is associated with higher vulnerability to functional decline and progressive disability, which in turn increase risk for CVD.
What is aging?
Although aging is customarily measured in chronologic years, more fundamental determinants of aging entail biologic stress over time (e.g., oxidative stress) in juxtaposition to diminishing homeostatic capacities contingent on telomeres, epigenetics, proteostasis, autophagy, and other subcellular factors. Cellular senescence and the related phenomenon of inflammaging, or chronic low-grade inflammation, also increase with age and catalyze development of CVD, comorbidities, and geriatric syndromes. Yet progression of subcellular aging phenomena and clinical manifestations are moderated by each person’s lifelong health habits (e.g., nutrition, physical activity, sleep, alcohol), CVD risk factors, comorbidities, social structure (e.g., spouse, children), and intrinsic functional capacities (e.g., physical, cognitive). Although chronologic years are immutable, other aspects of aging can often be modified. Habitual exercise and/or caloric restriction, for example, reduce the trajectory of aging and susceptibility to age-related CVD.
Age-Associated Changes in Cardiovascular Structure and Function
Normal aging is associated with alterations in cellular function, molecular signaling, proteostasis, and other mechanistic variations that lead to progressive changes in cardiovascular (CV) structure and function. These changes induce localized and systemic neurohormonal responses, such as release of proinflammatory cytokines and upregulation of the renin-angiotensin-aldosterone system, that set the stage for age-related CVDs ( Fig. 90.1 ).
Vasculature
Prominent structural and functional changes affect the arterial system in older adults, even among those with no apparent CVD. The arterial wall media thickens due to smooth muscle cell hypertrophy, extracellular matrix accumulation, and calcium deposition. Intimal-medial thickness (IMT) increases almost threefold between ages 20 and 90 years in normotensive individuals. The range of IMT also increases with age, suggesting a variable response to aging, likely due to different genetic and lifestyle factors.
Along with increased IMT, advancing age leads to fraying of elastic fibers as well as increases in collagen content and enzymatic cross-linking of extracellular matrix molecules in the arterial media that reduce distensibility and increase stiffness. Irreversible non-enzymatic glycation-based crosslinking of collagen forms advanced glycation end products (AGEs) that exacerbate the stiffening.
Changes in both vasodilating nitric oxide (NO) and vasoconstricting angiotensin II also contribute to vascular aging. Age-dependent reductions in endothelium-dependent vasodilation have been attributed to reduced NO production. Animal studies show both lower NO levels and reduced NO, consistent with reduced endothelial NO synthesis. Conversely, angiotensin II in the vessel wall increases 1000-fold with substantially increased angiotensin II signaling.
Both oxidative stress and chronic low-grade inflammation are key mediators of the structural and functional changes in the arterial wall with aging (see Chapter 24 ). Oxidative stress results from excessive generation of reactive oxygen species by enzymes such as NADPH oxidase, uncoupled NO synthase, and xanthine oxidase by the mitochondrial transport chain and from reduced antioxidant capacity. Increased reactive oxygen species and dysfunctional endothelial NO synthase contribute to age-associated decrements in endothelium-mediated vasodilation. Elevated oxidative stress also leads to enhanced protein oxidation, activation of inflammatory and endoplasmic reticulum stress responses, and apoptosis.
As a result of structural and functional changes in the arterial walls, stiffening of large- and medium-sized arteries occurs with aging, independent of disease. Systolic blood pressure (SBP) generally rises (see Chapter 26 ). In contrast, diastolic blood pressure (DBP) tends to rise until the sixth decade and declines thereafter due to reduced elastic recoil from the stiffer large arteries. Pulse pressure, the difference between SBP and DBP, also increases with age, augmenting the pulsatile load on the heart and vasculature Pulse wave velocity (PWV), the speed with which an arterial pulse wave traverses the arterial tree, is another index of arterial stiffness. Aorto-femoral PWV increases two- to threefold across the adult lifespan in normotensive populations (see Chapter 43 ).
Left Ventricular (LV) Composition and Mass
With aging there is a decrease in the total number of cardiomyocytes, likely due to apoptosis, and an increase in their individual size (i.e., hypertrophy). In both animal and human studies, apoptotic myocytes were more prevalent in the hearts of older men compared with women, paralleling an age-related decline of LV mass in men but not in women. Within the connective tissue, collagen content, fibrosis, and deposition of cardiac amyloid and lipofuscin all increase. The heart therefore becomes more fibrotic and stiffer with age.
LV Wall Thickness, Cavity Size, and Shape
Despite the absence of an increase in cardiac mass with aging, there is a significant increase in myocardial thickness due to increased cardiomyocyte size. Although concentric LV hypertrophy occurs, the interventricular septum increases in thickness more than the free wall, and there is a change in LV shape to a more spherical configuration. A more spherical ventricle is exposed to higher wall stress and is associated with higher incidence of LV dysfunction and HF (see Chapter 47 ). LV diastolic and systolic volumes decline with age and the LV mass/volume ratio increases in both sexes.
Resting Cardiac Function
In healthy normotensive adults, resting LV shortening fraction and LV ejection fraction (LVEF), the two most commonly used measures of global LV systolic performance, are not affected by age. Prolonged contractile activation of the thickened LV wall maintains a normal ejection time, and compensates for the late systolic augmentation of blood pressure (BP), preserving systolic LV pump function despite increased arterial stiffness. However, there is a modest decline in transmural global longitudinal strain and an increase in global circumferential strain with age. The increase in circumferential strain is likely a compensatory mechanism to maintain global LVEF.
In contrast to systolic function, LV diastolic performance is prominently altered by aging. Whereas LV diastolic filling occurs primarily in early diastole in younger adults, transmitral early diastolic peak-filling rate declines by 30% to 50% between ages 20 and 80 years. Conversely, there is an age-associated increase in peak A-wave velocity, which represents late LV filling facilitated by atrial contraction. The increase in late LV filling is mediated via a modest age-associated increase in left atrial size. Tissue Doppler imaging in older adults shows lower E, e’ and s’, and greater E/e’ compared with young individuals in both sedentary and trained persons.
Although age-related delays in early diastolic filling rate do not usually compromise end-diastolic volume and stroke volume at rest, stress-induced tachycardia (e.g., with exercise, fever, or other physiologic stress) is likely to exacerbate diastolic filling abnormalities. Tachycardia not only disproportionately shortens the time available for diastolic filling but also exacerbates impaired energy-dependent uptake of calcium into the sarcoplasmic reticulum. Therefore, fast heart rates are commonly associated with diastolic filling abnormalities, and the higher LV diastolic pressure is transmitted into the lungs despite normal resting LV systolic function. These findings are commonly manifested as HFpEF, especially when superimposed on other common age-associated comorbidities such as hypertension, diabetes, coronary heart disease (CHD), and atrial fibrillation (AF) (see Chapter 51 ).
The enlargement of the left atrium that occurs as a function of age and diastolic dysfunction occurs primarily after age 70 years and increases susceptibility of older adults to AF. Whereas AF is often well tolerated in younger adults, it is more likely to provoke symptoms and clinical events among older individuals. Not only is AF commonly associated with poorly tolerated fast ventricular rates, but the AF-induced loss of the atrial boost to diastolic filling aggravates age-related diastolic filling impairment. Thus, older patients with AF are more likely than younger patients to incur reduced cardiac output and resultant dyspnea and fatigue (see Chapter 66 ).
Age-associated myocardial changes also predispose some older adults to myocardial ischemia and HF. A thicker LV predisposes to subendocardial ischemia by increasing the distance between the epicardial coronary arteries and the subendocardial myocytes. In addition, capillary growth and flow regulation in older hearts may not match the oxygen demands of the hypertrophied myocytes. These intramyocardial changes in capillarity and flow-dynamics are compounded by peripheral arterial stiffening and accelerated PWV (i.e., faster reflected pressure waves in systole), such that subendocardial perfusion is no longer bolstered by augmented pressures in diastole, leading to a decline in coronary perfusion pressure.
Amidst the aforementioned age-associated changes in the vasculature and heart ( Table 90.1 ), especially when compounded by prolonged exposure to other CVD risk factors, CVD increases markedly in older adults. Intrinsic vulnerability to atherosclerosis in the vasculature predisposes to myocardial ischemia, MI, stroke, and peripheral arterial disease (PAD). Heart failure with reduced ejection fraction (HFrEF) may develop as the result of ischemic coronary events or prolonged hypertension, either of which can impair LV systolic function. However, HFpEF is more likely to develop in the setting of ventricular stiffening, especially in association with hypertension, AF, and diabetes, all of which increase with age. Furthermore, CV aging occurs in a context of other age-related changes that compound the effects of CVD ( Table 90.2 ) (see Chapter 51 ). Risks associated with myocardial ischemia, HF and other CVD become significantly worsened in the presence of concomitant renal, metabolic, hematologic, pulmonary, and other noncardiac physiologic changes.
TABLE 90.1
Relationship of Cardiovascular Aging in Healthy Humans to Cardiovascular Disease
| Age-Associated Changes | Plausible Mechanisms | Possible Relationship to Disease |
|---|---|---|
| CV Structural Remodeling | ||
| ↑Vascular intimal thickness | ↑ VSMC migration | Early stages of atherosclerosis matrix production |
| ↑ Arterial stiffness | Elastin fragmentation and ↑ elastase activity | Systolic hypertension |
| ↑ Collagen production and cross-linking | ||
| Altered growth factor regulation and tissue repair | Atherosclerosis | |
| ↑ LV wall thickness | ↑ LV myocyte size | ↓ Early LV diastolic filling |
| ↓ Myocyte number and focal collagen deposition | ↑ LV filling pressure/dyspnea | |
| ↑ Left atrial size | ↑ Left atrial volume and pressure | ↑ Risk of atrial fibrillation |
| Calcium deposits in valves and conduction system | Mechanical stress | Aortic stenosis Atrioventricular block |
| CV functional changes | ||
| Altered vascular tone | ↓ NO production/effects ↓ βAR responses |
Vascular stiffening and hypertension |
| ↓ CV reserve | ↑Vascular load | Lower threshold for heart failure |
βAR , Beta adrenergic receptor; CV , cardiovascular; LV , left ventricular, VSMC , vascular smooth muscle cell.
TABLE 90.2
Common Age-Related Changes that Compound CVD Risks
| Kidneys | ↓ Glomerular filtration rate ↓ Renal metabolism |
| Lungs | ↓ Ventilatory capacity ↑ Ventilation/perfusion mismatching |
| Musculoskeletal | ↓ Skeletal muscle mass and function (sarcopenia) ↓ Protein reserves ↓ Bone mass |
| Immune function | ↑ Susceptibility to infections |
| Hematopoietic | ↑ Levels of coagulation factors ↑ Platelet aggregability ↑ Inhibitors of fibrinolysis ↑ Anemia |
| Neurohormonal | ↓ Cerebral autoregulatory |
| Liver | ↓ Hepatic metabolism |
| Mood | ↑ Depression ↑ Anxiety |
| Sleep | ↑ Obstructive sleep apnea |
CV Response to Exercise
The ability to perform physical activity is highly relevant in clinical evaluation, especially in older adults. The CV response to aerobic exercise remains useful as a diagnostic and prognostic tool and is also strongly predictive of the ability of older individuals to withstand major procedures or aggressive therapies (see Chapter 32 ).
Aerobic Exercise Capacity
Cardiorespiratory fitness (defined by oxygen consumption [VO 2 ] max per kg weight at peak exercise) declines progressively with age. In cross-sectional studies, the decline is ∼50% from the third to ninth decade. In longitudinal studies, a more pronounced age-associated VO 2 max decline is evident, regardless of habitual physical activity levels ( Fig. 90.2 ). The decline is only partially explained by changes in maximal heart rate and other CV parameters. Sarcopenia (i.e., atrophy and weakening of skeletal muscle) contributes significantly to age-associated decrease in VO 2 max. Age-related sarcopenia involves reduced number, size, and function of muscle fibers. By age 75 years, muscle mass typically represents ∼15% of body weight compared with 30% in young adults. Fast twitch fibers atrophy to a greater extent than slow twitch fibers, which likely contributes to decrements in strength that are proportionally greater than the loss of muscle mass. Increased intramuscular fat and decreased mitochondrial bioenergetics contribute to reduced muscle function. Furthermore, CVD has additional effect on skeletal muscle (most notably in HF) that compound impact of sarcopenia.
The accelerated decline of aerobic capacity with age has important implications regarding functional independence and quality of life (QOL). Because many of the activities of daily living require fixed aerobic expenditures, they require a significantly larger percent of VO 2 max in older than younger adults. When the energy required for an activity approaches or exceeds the aerobic capacity of an older individual, he or she will be less able and likely to perform it.
Cardiac Function During Aerobic Exercise
In healthy adults, a ∼50% decline in peak VO 2 between ages 20 and 80 years is accompanied by ∼30% declines in cardiac output and ∼20% declines in arteriovenous oxygen uptake. The decrease in cardiac index with age at maximal effort is due primarily to reduced heart rate. Older individuals also have blunted capacity to reduce LV end-systolic volume (ESV) and to thereby augment LVEF with exercise to sustain higher capacity function (in part due to an age-related decline in adrenergic responsiveness). Some studies suggest this deficit may be offset by achieving a larger end-diastolic volume (EDV), that is, the slower heart rate allows more time for LV filling, thereby providing a greater amount of blood in the heart at end-diastole. Nonetheless, maximum maximal LVEF often still diminishes with age due to insufficient diastolic expansion, reduced intrinsic myocardial contractility, increased arterial afterload, arterial-ventricular load mismatching, and blunted sympathetic modulation of LV contractility and arterial afterload. , The net effect of these changes is a marked reduction in CV reserve, such that even healthy older individuals free of CVD tend to become less able to maintain CV homeostasis in response to stress (e.g., major surgery or acute illness).
Geriatric Domains Pertinent to Cardiovascular Care
As described above, geriatric syndromes develop from the same biologic milieu as CVD in older adults. CVD in old age is likely to occur in combination with geriatric health care challenges that confound the standards of care that pertain primarily to younger and/or relatively more robust older populations ( Table 90.3 ).
Multimorbidity
Multimorbidity or “multiple chronic conditions” denotes a situation in which two or more chronic conditions are active simultaneously. Multimorbidity shifts the therapeutic paradigm away from one that is oriented primarily to CVD-specific care to one that considers CVD in the context of competing conditions and priorities. For CVD therapies to achieve outcomes perceived as beneficial by a patient with multimorbidity, they must remain effective amidst conditions for which they were not intended or studied.
Multimorbidity, prevalent in more than 70% of adults age ≥75 years and in up to 90% of older HF patients, challenges the basic principles underlying conventional CV management. “Evidence-based” CVD guidelines typically rely on investigations that excluded study populations with significant comorbidities. Traditional therapy may be less applicable to patients with multiple diseases and concomitant medications. In a study of Medicare patients, in those with HF, stroke, or AF, 50% had five or more comorbidities ( Fig. 90.3 ). Moreover, the number of comorbidities correlates strongly with hospitalizations, cost of care, and mortality.
Management of CVD must be considered with added precautions as conventional therapies may provoke adverse effects; for example, antihypertensive medications are more likely to provoke falls in older patients with sarcopenia, Parkinson disease, or vision impairment. Furthermore, outcomes of older patients with CVD are often more likely to be affected by non-CVD comorbidities. For example, rehospitalization for HF may be caused by an infection or renal disease.
Frailty and Sarcopenia
Frailty denotes a state of vulnerability to stressors with limited reserves to stabilize declines across multiple physiologic systems. Prevalence of frailty ranges from 10% to 70% in different CVD populations. Frail adults are prone to developing CVD and have worse outcomes and greater risks for harmful sequelae from standard therapies. With the advent of transcatheter aortic valve replacement (TAVR), interest in frailty accelerated among cardiology proceduralists as frailty often serves as a key selection criterion by which TAVR is considered (see Chapter 74 ). Subsequently, in the importance of frailty in informing personalized management has expanded to include care for acute coronary syndromes (ACS), CHD, and many other types of CVD.
While the optimal assessment tool for frailty remains undefined, frailty is increasingly thought to be a biologic manifestation of inflammation ; circulating inflammatory biomarkers (high-sensitivity C-reactive protein and interleukin [IL]-6), as well as inflammatory cells (neutrophils and monocytes) are increased in frail individuals. Thus, CVD and frailty share inflammatory pathophysiology and tend to occur together. Older adults with CVD are more likely to be frail, and vice versa. Although geroscience insights implicate multiple subcellular mechanisms, cellular senescence and associated inflammaging are significant components, , linking CVD, multimorbidity, frailty, and sarcopenia.
Sarcopenia is defined as a reduction in muscle strength and mass that is abnormally severe for an individual’s age. Whereas muscle atrophy is common with aging, sarcopenia entails muscle atrophy and weakening (dynapenia) that tends to be more common amid frailty and CVD. Inflammation is associated with reduced synthesis and activity of insulin-like growth factor 1 (IGF1), essential for muscle regeneration and maintenance of muscle integrity, and that also plays a role in mitigating plaque instability in atherosclerosis. In observational studies, high levels of IL-6 and low levels of IGF1 correlate with lower muscle strength and power, predicting frailty and associated risks of disability and death.
Two general approaches to identify frailty have evolved : frailty conceptualized as an observable phenotype and frailty conceptualized as a numerical index. Fried advanced the premise of a “frailty phenotype” by identifying five specific physical characteristics that could be systematically assessed: weakness, low energy, slowed walking speed, decreased physical activity, and weight loss. Rockwood has championed an alternative approach in which frailty is conceptualized as an “index” of deficits of candidate variables, that is, a ratio of physical deficits as well as morbidities, disability, and other clinical variables that accumulate and progressively burden an individual. The magnitude and speed that deficits accumulate is applied as a gauge of vulnerability and risk. Variations on Fried’s composite of physical phenotypic features include single-measure performance assessments including gait speed, handgrip strength, balance, or chair rise. Composite assessments such as the Timed Up and Go (TUG) and Sit to Stand tests are also popular as they integrate multiple functional capabilities but usually entail more time and training to administer. A frailty tool app developed by Afilalo demonstrates their application ( https://apps.apple.com/us/app/frailty-tool/id1330330931 ).
Cognitive Impairment
Whereas dementia affects fewer than 5% of the population at 65 years, it affects more than 40% of those living past 85. Prevalence is even higher in those with CVD, with causal relationships attributable to vascular disease, HF, AF, hypertension, hypotension, and frailty; relevant pathophysiology includes perfusion abnormalities, thrombosis, inflammation, mitochondrial dysfunction, and other factors. For many older adults, cognitive decline may be insidious and subtle, often masked by a protective family and/or by a gradual withdrawal from activities and engagements that were previously routine. For those with overt dementia as well as those with subtle progressions of dementia, managing CVD often becomes disproportionately challenging. Clinical challenges relate to eliciting symptoms and past medical histories, making informed decisions, navigating diagnostic testing and procedures, and achieving reliable adherence and follow-up. Formalized testing of cognition may provide value, especially when cognition changes are subtle. Screening with the Montreal Cognitive Assessment (MoCA), Mini-Mental State Exam (MMSE), and miniCog are feasible options that can be integrated as part of CV care, with referral to a geriatrician or neurocognitive expert for further evaluation if indicated.
Delirium
Delirium is a disorder of disturbed attention that can manifest as agitated disruptive behavior or as quiet and withdrawn behavior that is less likely to elicit attention and corrective response. Delirium occurs in one-third of hospitalized patients ≥70 years, including 50% of those undergoing cardiac surgery and over 75% of those who require mechanical ventilation in an intensive care unit (ICU) (see “Special Considerations” under “Noncardiac Surgery and Perioperative Management Considerations In Older Adults”). Baseline cognitive impairment significantly increases risks that delirium may occur. Mortality, morbidity, length of stay, cost, and discharge to a facility are all increased in those who become delirious. Multiple factors of hospitalization are likely to trigger it, including the stress of a new environment, poor sleep, new medications, withdrawal from home medications, pain, dehydration, hypoxia, and metabolic shifts. Anticipatory screening by the Confusion Assessment Method (CAM) is a validated tool for screening in a hospital setting and provides opportunity to mitigate precipitating factors.
Polypharmacy
Polypharmacy is common among older adults, with significant and sometimes dire consequences. The Sloan survey showed that 44% of older men and 57% of older women received five or more prescription medications. In some cases polypharmacy relates to multimorbidity as multiple clinicians prescribe evidence-based medications oriented to different diseases. While disease guidelines are each supported by evidence, there is no guideline that addresses medications amidst multiple concurrent diseases and aggregate medical regimens. Nonetheless, “quality indicators” used to assess the quality of care for individual diseases commonly reinforce tendencies for clinicians to prescribe guidelines-based medications irrespective of comorbidity and the total number of medications the patient is taking. Although most CVD guidelines acknowledge that clinical judgment is necessary to integrate evidence-based standards with each patient’s circumstances, they do not provide a refined strategy to achieve such tailored care.
The safety risks associated with mounting numbers of medications in older adults are also affected by age-related changes in pharmacokinetics and pharmacodynamics (see Chapter 9 ). The most significant age-related changes of pharmacokinetics pertain to renal metabolism. Glomerular filtration rate (GFR) decreases about 10% per decade in men and women. By age 80 years, GFR is typically one-half to two-thirds of that in younger adults. This reduction can be masked by overestimation of GFR using the Modified Diet in Renal Disease (MDRD) formula and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI). The Cockroft-Gault is usually a preferred GFR equation; it accounts for age, sex, and weight, and characterizes a linear decrease of renal function. The dosage of many medications cleared by the kidney must be reduced in older patients with impaired renal function (e.g., digoxin, low-molecular-weight heparin [LMWH], glycoprotein IIb/IIIa inhibitors and, in some cases, direct-acting oral anticoagulants [DOACs]) (see Chapter 101 ).
Pharmacodynamic alterations are especially common amidst age-related changes in neuroautoregulation. Changes in thirst, temperature regulation, autonomic reflexes, sympathetic and cholinergic receptors, and cell signaling all impact the effects of medications, with greater susceptibility to orthostasis, syncope, falls, and other clinical sequelae.
Drug–drug interactions are typical amidst polypharmacy, particularly when medications are metabolized by the same pathway. Amiodarone, for example, inhibits CYP oxidative enzymes and increases drug levels of those medications that would normally be metabolized by this pathway (see Chapter 9 ). Adverse effects may also occur if clinical actions of medications are additive (e.g., administering aspirin, clopidogrel, and apixaban together will exacerbate bleeding risks) or competing (e.g., administering liraglutide and steroids together will decrease glucose control).
Drug–disease interactions occur as medications that benefit one chronic disease adversely affect another disease or syndrome. Beta blockers for cardiac ischemia may, for example, trigger bronchospasm in patients with concomitant chronic obstructive pulmonary disease (COPD). Calcium channel blockers can exacerbate chronic constipation, which is usually further compounded by sedentariness. Diuretics can aggravate incontinence and related social isolation and depression.
Disability
Disability refers to a physical or mental condition that limits a person’s movements, senses, or activities. Whereas younger adults with CVD are usually able to rebound after a successful CVD hospitalization or therapy, an older adult has greater risks of new or worsening disability. Multimorbidity, frailty, sarcopenia, polypharmacy, and other geriatric syndromes predispose to disability in hospitalized older adults, especially in the context of deconditioning, cognitive impairment, malnutrition, and other burdens in older patients with CVD. The impact of hospital-related disability is widespread and in some respects paradoxical, as older adults are especially vulnerable to morbid effects from the hospitalizations that are used to deliver care.
Notably, many CVD guideline-based therapies may inadvertently increase susceptibility to disability (e.g., increasing myalgias with statins and/or fatigue with beta blockers) especially among adults. Recent CV trials reflect the growing recognition that the therapeutic priorities of many older patients differ from those who are young. In the ASPirin in Reducing Events in the Elderly (ASPREE) trial, instead of focusing principally on thromboembolic events, bleeding and other disease metrics, the main endpoint was a “disability-free life,” including freedom from dementia, for which there was no benefit of aspirin therapy.
TABLE 90.3
Geriatric Syndromes and Clinical Implications
| Geriatric Syndrome | Diagnosis/Prevalence | Prognosis | Disease Management |
|---|---|---|---|
| Multimorbidity | Two or more chronic conditions (cardiac and noncardiac) that are active simultaneously Prevalence: 63% of those 65-74 years of age, 77% of those 75-84 years of age, and 83% of those ≥85 years of age |
↑ Short and long-term prognostic risks due to CVD as well as non-CVD instability | Confounds customary CVD symptoms and signs Multiple diseases and providers often result in desynchronized or even contradictory aspects of care ↑ Likelihood that patients will experience high therapeutic burden |
| Frailty | State of vulnerability relating to diminished physiologic reserves across multiple physiologic systems Definition controversial: some define frailty as a phenotype, whereas others define frailty as an index of cumulative clinical deficits Prevalence: ranges from 10% to 60%, depending on the CVD burden, as well as the tool and cutoff chosen to define frailty. |
↑ Risk from CVD as well as medical, device, percutaneous catheter, and surgical therapies used to treat CVD. ↑ Risks disability, falls, rehospitalization, poor quality of life, mortality |
Guidelines-based therapy and procedures commonly overlook the impact of frailty on recommendations. Intensive care, bed rest, and functional decrements associated with many conventional therapies can exacerbate frailty and functional decline. Nutrition and exercise may help mitigate frailty and risks of frailty |
| Cognitive decline | Mild cognitive impairment (MCI)→ ↓ cognitive function without loss of function Prevalence estimates vary with the population and methods, but it rises with age, generally in the range of 2%-5% in those 60-55 to >20%-40% in those ≥90 years. Dementia → severe memory loss that interferes with daily life and loss of functional independence Prevalence increases with age, from ∼5.0% of those aged 71-79 years to 35%-40% of those aged 90 and older. |
↓ Independence ↓ Adherence ↓ Shared decision making ↓ QOL ↑ Hospitalization ↑ Mortality |
Often confounds assessments of symptoms Often confounds accounts of present illness and PMHx Often confounds adherence Does not negate the potential value of therapeutic intervention, but it impacts the decision and implementation process |
| Delirium | Disturbance in cognition, attention, and consciousness or perception with fluctuating course Can manifest as agitated state or quiet and withdrawn High prevalence in older adults who are hospitalized, i.e., ∼30%-60%. |
↑ LOS ↑ Rehospitalization ↑ Functional decline ↑ Falls ↑ Long-term care ↑ Mortality |
Predisposing risks include cognitive deficit, sensory limitations, and disorienting medications Treat by optimizing environment to increase orientation, avoid sedation, reduce meds, reduce pain |
| Polypharmacy | Multiple medications that have unintended interactive effects Polypharmacy usually considered four or more chronic medications 40% of older adults take ≥4 medications |
↑ Adverse events (errors and drug interactions) ↑ Rehospitalizations ↑ Mortality |
↑ Medication errors ↑ Drug–drug and drug–body interactions ↓ Adherence is common ↑ Under- and overtreatment both commonly occur Deprescribing is a relevant consideration |
| Disability | The inability to care for oneself or to manage one’s own home | ↑ Risk progressive functional and cognitive declines ↓ Self-reliance and self-efficacy ↑ Long-term care ↑ Mortality |
Conventional care for CVD often contributes to a cycle of progressive disability, which highlights rationale for shared decision making for each aspect of therapy Suboptimal transitions are common contributors to disability, (e.g., hospital to home, and even hospital to postacute care) |
| Sensory loss | Vision and hearing deficits are common | ↑ Risk progressive functional and cognitive declines ↓ Self-reliance and self-efficacy ↑ Long-term care ↑ Mortality |
Conventional care for CVD often contributes to a cycle of progressive disability, which highlights rationale for shared decision making for each aspect of therapy Suboptimal transitions are common contributors to disability, (e.g., hospital to home, and even hospital to postacute care) |
| Incontinence | Urinary incontinence is common and often worsened by diuretics and other CVD meds | ||
| Falls | Falls are common in older CVD patients as they can be provoked by environmental as well as syncopal etiologies and are often exacerbated by other geriatric syndromes such as polypharmacy, frailty, delirium, and visual deficits |
Precepts of Patient-Centered Care in Older Adults
Although there is a tendency to refer to older adults as a distinct population with uniform health challenges, the variability between patients increases with age. Over a lifetime each individual encounters a diverse array of experiences, engages in a wide range of behaviors affecting health for better or worse, accumulates a highly variable list of health conditions of differing severity and impact, develops individualized attitudes about health care and preferences for care, and does all of these things in the context of uniquely personal psychosocial and family dynamics. As a result, people become progressively more heterogeneous with age. A fundamental challenge in caring for older patients with CVD is to integrate all of these factors, including prevalent geriatric syndromes, into a management plan that provides greatest weight to what is most important to the patient while maintaining sensitivity to competing non-CV comorbidities and social milieu that may greatly influence the patient’s health care goals.
Diagnosis and Risk Assessment
Older adults are at increased risk for CVD due to age-related changes in CV physiology and the high prevalence of traditional CV risk factors at older age, especially hypertension, dyslipidemia, diabetes, obesity, and sedentary lifestyle. However, older patients are also more likely to have ambiguous symptoms (i.e., symptoms with multiple often coexisting potential causes), atypical symptoms, or no symptoms despite advanced disease. Thus, a high index of suspicion for CVD is appropriate, and the clinician should be alert for subtle signs and symptoms that might suggest a new or worsening CV disorder. For example, a change in activity level or alterations in mood, cognition, or sleep and eating habits may reflect HF, severe CHD, or AF. Conversely, these same symptoms could be due to a host of other conditions, including depression, pulmonary or thyroid disease, or medication side effects. It is incumbent on the clinician to consider these possibilities before ordering a battery of diagnostic tests. Test selection, when indicated, should also include consideration of the clinical implications of test results. While this is true in patients of all ages, it is a consideration that becomes more germane in older adults. For example, an echocardiogram that is clearly warranted to assess LVEF to determine eligibility for an implantable cardioverter-defibrillator (ICD) in a middle-aged patient with HF becomes inappropriate for an 87-year-old woman who indicates that she does not want an ICD or in an older adult with limited life expectancy due to advanced comorbid illness.
Disease Management and Care Coordination
Given the likelihood of CVD occurring in a context of multimorbidity, most older patients have multiple providers, including physicians, advanced practice nurses, physician assistants, pharmacists, nutritionists, and therapists. While multiple providers offer complementary expertise, they predispose to fragmented care. The potential for mixed messaging, conflicting therapeutic plans, patient confusion, polypharmacy, and nonadherence is high. Although the primary care provider often assumes the role of medical “quarterback” to integrate care across multiple providers, decisions regarding medications, devices, procedures, and ongoing monitoring typically require CV expertise. Thus, CV clinicians must be skilled to work within such complex team relationships. Effective interpersonal skills and organization are increasingly requisite for effective CV care in older patients.
Application of Guidelines
Evidence-based practice CVD guidelines are based principally on randomized clinical trials in which older patients are under-represented; those who are enrolled tend to be healthier with fewer comorbidities and geriatric syndromes than those encountered in clinical practice. An additional limitation of guidelines is that recommendations are generally disease-specific and fail to adequately consider the impact of multimorbidity, cognitive impairment, or frailty. Other factors that may limit the relevance of guidelines to older patients include time-to-benefit versus time-to-harm, life expectancy, and patient burden. For many therapies, time-to-benefit is delayed, whereas adverse events may occur early during treatment. For example, ICD implantation is associated with an upfront procedural risk that is higher in patients ≥80 years, whereas the lifesaving benefit of an ICD may be delayed for years, if it occurs at all. Similarly, medication side effects often occur early after initiation, but benefit may not accrue for months to years. In the same way, patients with limited life expectancy due to very advanced age (i.e., ≥90 years) or competing illness may not survive long enough to derive benefit from some treatments. In addition, adherence to guideline recommendations often imposes burden on patients in the form of testing or additional medications that the patient, given the choice, would opt to forego. Importantly, in recent years many CV guidelines have acknowledged the above limitations and have advocated shared decision making in situations where applicability of recommendations is uncertain.
Shared Decision Making
Shared decision making (SDM) is a process by which an informed patient actively participates in decisions affecting the patient’s health care. The role of the clinician is to initially provide an unbiased summary of available options including advantages, disadvantages, and implications (in the case of testing). Following discussion with attention to patient concerns and questions, as well as incorporation of goals of care (e.g., QOL vs. length of life) and health care preferences (e.g., avoidance of risk and minimization of burden vs. willingness to accept risk and burden to achieve primary goal), a decision is made jointly by the patient (and family if appropriate) and the provider ( Fig. 90.4 ). In most cases, decisions are not irrevocable and can be modified as circumstances, such as symptoms and comorbidities, evolve. In many cases, older patients, after being informed of the options and asking questions, will seek guidance from the clinician in reaching a decision. At this point, it is appropriate for the clinician to make a recommendation that is best aligned with the patient’s goals and preferences.
Care Transitions, Skilled Nursing Facilities, and Long-Term Care
Care transition refers to any change in location of care delivery, for example, from hospital to postacute care or from skilled nursing facility to home. Older adults, especially those with multimorbidity, cognitive impairment, or frailty, are especially vulnerable to adverse outcomes during care transitions, including functional decline, medication errors, and delirium. These perturbations often lead to rehospitalization and spiraling functional decline and progressive disability. To reduce the risk of adverse outcomes, effective care coordination is essential. In particular, meticulous medication reconciliation is required to ensure that the patient is taking all appropriately prescribed medications, but no medications that have been discontinued or which are no longer indicated. Minimizing polypharmacy and attention to potentially inappropriate medications in older adults, as defined by the Beers Criteria, is especially important. A clinical pharmacist with experience in geriatric prescribing can play an invaluable role in ensuring safe and effective drug prescription and better medication adherence. Additional interventions that facilitate successful care transitions include frequent in-person or telephone follow-up and continuity of the care provider before, during, and after the transition.
The role of postacute care for CVD patients is changing. In the past, older and sicker patients were routinely hospitalized for prolonged periods and were stable upon discharge to postacute care. As contemporary incentives encourage more rapid discharges from acute hospitalizations, increased numbers of older CVD patients are being discharged to skilled nursing facilities (SNFs). Of the more than 1 million hospital discharges for HF each year in the United States, approximately 20% are discharged to SNFs. These patients often have residual volume overload, fluctuating renal function, and evolving medication regimens. Yet SNF staff often lack adequate training and are uncomfortable caring for moderately ill and potentially unstable CVD patients. In addition, systematized access to CVD clinicians may be limited. CMS has imposed mandatory quality metrics for SNFs to improve and standardize care, but apart from medication review, these metrics are not directly applicable to CV conditions.
CVD is highly prevalent in patients in long-term care facilities. This is a particularly vulnerable population with high prevalence of cognitive dysfunction, physical disability, frailty, and multiple coexisting medical conditions. However, data on optimal management of CVD in long-term care residents is sparse, as these patients have routinely been excluded from CV trials and few observational studies have focused on this group.
Palliative Care and End-of-Life Care
Palliative care focuses on alleviating symptoms, reducing physical and emotional suffering, and improving QOL; these are integral components of almost all medical care. In addition to managing symptoms, palliative care addresses psychosocial and spiritual needs. It provides an extra layer of support, often in association with standard care. Palliative care improves QOL and may increase survival. It is distinct from hospice care, which is oriented to patients with a prognosis of <6 months of expected survival, and who have agreed to forgo more aggressive treatment.
In some respects, geriatric cardiology and palliative care overlap. Many patients referred for palliative care are older and have CVD in the context of frailty, disability, and other care complexities that require a tailored approach to CV management. Although palliative care does not preclude standard care, including procedures such as percutaneous coronary intervention (PCI) or TAVR that may markedly improve QOL, most patients who choose to pursue palliative care have prioritized QOL and comfort over length of life. In other situations, geriatric cardiologists are at the crossroads of management and must facilitate decisions about which older, complex, frail patients may still benefit from prevention and intervention strategies that may forestall or reverse decline.
Among people ≥75 years, CVD is the leading cause of death, exceeding all other causes of death combined. As a result, CV providers and their patients often face end-of-life decisions, including decisions about resuscitation, thresholds of futility, and strategies to help families/surrogate caregivers if patients lose capacity to make their own decisions. In most instances it is effective to encourage and support older adults to develop an advance directive, clarifying what medical care they would or would not want in the event of a life-threatening or terminal illness, as well as designating durable power of attorney for health care. It is also useful when patients discuss these issues with their families or health care proxies so that there is clear understanding of their preferences. It is helpful for clinicians of older patients with CVD to initiate these discussions as part of routine care delivery (i.e., “normalize” the conversation). Studies have shown that most patients, especially those with advanced symptoms (e.g., New York Heart Association [NYHA] Class III–IV), prefer having these conversations with their trusted clinicians.
Deprescribing
Deprescribing is the process of reducing the dose or discontinuing medications that have become burdensome to the patient (e.g., due to side effects), are no longer aligned with the patient’s goals of care, or are no longer likely to provide benefit or to have a favorable benefit-to-risk ratio. Deprescribing is an integral component of good prescribing practice with the goals of reducing medication burden, decreasing risk of drug–drug and drug–disease interactions, and eliminating medications no longer likely to be beneficial or consistent with patients’ goals and preferences. Older adults with declining life expectancy, high self-perceived medication burden, advanced dementia, or multiple competing comorbidities are good candidates for deprescribing, but even more vigorous adults can potentially benefit. Care transitions with comprehensive medication reconciliation offer an excellent opportunity for deprescribing, but all contacts with providers should include a medication review with consideration of medications that might be discontinued.
Coronary Heart Disease
Epidemiology
Age-related vascular changes in conjunction with increasing prevalence and duration of traditional cardiac risk factors predispose to the development of CHD at older age, and age is the strongest risk factor for incident CHD (see Chapter 25 ). Similarly, the prevalence and mortality rates of CHD increase progressively with age. The Global Burden of Disease Study indicates that in men, approximately 50% of deaths attributable to CHD occur in those over age 70, whereas in women, almost 50% of CHD deaths occur among those over age 80.
Presentation
Compared with younger individuals, older adults with stable CHD, especially those over age 80, are less likely to experience exertional angina and more likely to report shortness of breath, fatigue, or lack of energy as manifestations of myocardial ischemia. Similarly, dyspnea is the most common presenting symptom of acute MI in patients over age 80, and the prevalence of atypical symptoms, including indigestion, dizziness, and altered mentation increases with age. In addition, many older patients with CHD are asymptomatic, in part due to sedentary lifestyle, and the incidence of silent or clinically unrecognized MI increases with age (see Chapter 35 ). Older patients also tend to minimize symptoms or attribute them to age or other causes, especially when comorbid diseases complicate the experience.
Risk Stratification and Diagnosis
Neither the Pooled Cohorts Equations nor the Framingham Risk Score permit estimation of risk for CVD events in patients ≥80 years, but even in the absence of other risk factors or symptoms, patients in this age group are at increased risk. Similarly, the majority of men over age 65 and women over age 70 in the United States are in the intermediate risk category, as defined by current guidelines. Further risk stratification in older adults thus requires consideration of concomitant risk factors and symptoms.
The decision to pursue CHD evaluation in older adults is predicated on the pretest likelihood of disease, the probability that the test results will alter management, and patient preferences. In patients with relatively low pretest likelihood of severe CHD, mild to moderate symptoms that could potentially be controlled with medications, or clearly stated preference to avoid testing if possible, a conservative approach designed to control symptoms and risk factors is appropriate. For other patients, the decision-making process should start with a discussion of the advantages, disadvantages, and limitations of further testing in the context of the patient’s goals of care. Results of two recent trials can be used to inform these discussions. In the PROMISE trial, 10,003 symptomatic patients with intermediate pretest likelihood of CHD were randomized to anatomical testing with coronary computed tomographic angiography (CCTA) or to functional testing (i.e., a stress test). Over a median follow-up of 25 months, the primary outcome of death, MI, hospitalization for unstable angina, or major procedural complication occurred in 3.3% of the CCTA group and 3.0% of the stress test group, with no difference between groups and similar findings in patients younger or older than age 65. These findings indicate that the risk of a major adverse cardiac event during a 2-year follow-up period is quite low, and suggest that a conservative strategy, without testing, is reasonable for patients who prefer to avoid testing. The second study, the ISCHEMIA trial, randomized 5179 patients with moderate to severe ischemia on stress testing to an initial invasive strategy with coronary angiography and revascularization if indicated, or to an initial conservative strategy with intensive medical therapy. Over a median follow-up of 3.2 years, there was no difference between groups in the primary outcome of CV death or MI, with similar findings across age groups. Patients randomized to the invasive strategy had better QOL, especially if they were more symptomatic at baseline. These results again provide rationale for conservative management, even in patients with moderate to severe symptoms, if the patient prefers to avoid testing and subsequent procedures.
In older patients who chose to proceed with further testing, the indications for stress testing, CCTA, and invasive angiography are similar to those in younger patients. If feasible, an exercise stress test is preferable to pharmacologic stress testing due to the important information derived on functional status, hemodynamic response to exercise, and occurrence of exercise-induced arrhythmias. If appropriate, the exercise protocol should be modified to accommodate lower exercise capacity in older adults (i.e., starting at lower intensity and using smaller workload increments). Coronary CT angiography is less accurate in assessing lesion severity in older patients due to their high prevalence of coronary artery calcium (CAC).
Management
Management of CHD (see Chapter 40 ) is similar in older and younger patients and includes control of risk factors, alleviation of symptoms, and prevention of complications (i.e., MI, death). Older patients are at increased risk for adverse effects from most medications, including bleeding with aspirin and other antithrombotic agents; bradycardia and hypotension with beta blockers; bradycardia, hypotension, pedal edema, constipation, and incontinence with calcium channel blockers (agent-specific); impaired renal function and hyperkalemia with ACE inhibitors (ACEI) and angiotensin receptor blockers (ARBs); and postural hypotension with nitrates. Statins in moderate- and high-intensities are recommended for adults >75 years, but risks of myalgias, fatigue, and reduced physical activity are increased.
Invasive coronary angiography and revascularization are recommended for older adults with refractory symptoms, particularly those with significant ischemia on noninvasive diagnostic tests. In the Trial of Invasive versus Medical therapy in Elderly patients (TIME) study, symptom relief and exercise capacity during 4-year follow-up were better with revascularization than with optimized medical therapy alone in older patients with CHD. Similarly, the ISCHEMIA trial demonstrated improved QOL with revascularization in patients with high symptom burden.
In older adults, PCI is associated with a modestly higher rate of procedural complications than in younger adults, including bleeding, stroke, and contrast-induced kidney injury. Dual antiplatelet therapy is associated with increased bleeding and transfusion risk in older patients. Bleeding risks can be minimized by using the radial artery approach and by weight- and renal dose-adjustments of anticoagulant and antiplatelet agents.
The choice of PCI versus coronary artery bypass grafting (CABG) involves consideration of the anatomy, comorbidities, functional capacity, frailty, and patient preferences. Although studies suggest that CABG is usually associated with less recurrence of symptoms and need for repeat revascularization, it also usually requires longer recovery and has a higher risk of stroke and procedure-related neurologic complications, including postoperative delirium. Patients with diabetes or left main disease appear to have superior long-term outcomes with CABG. Although persistent cognitive decline following CABG has been reported, studies indicate this may primarily reflect unrecognized prior cognitive dysfunction.
In assessing perioperative risk in older adults, physiologic status has greater import than chronologic age. The Euro SCORE and the Society of Thoracic Surgery (STS) risk score now include metrics of mobility and frailty (gait speed), respectively, in addition to surgical parameters and comorbidities, to help gauge short-term procedural risks and longer-term QOL outcomes. As discussed later (see “Cardiac Rehabilitation”), cardiac rehabilitation is also an integral component of CHD management.
Ischemia with Nonobstructive Coronary Arteries (INOCA)
INOCA is a multifactorial vascular syndrome in which an imbalance between oxygen supply and demand leads to ischemia in the absence of obstructive CHD. Increasing age and age-related arterial stiffness are risk factors for INOCA, particularly in women, which in turn is associated with increased risk for CV events and impaired QOL. Many older adults have coronary microvascular dysfunction and diminished coronary flow reserve, as detected by positron emission tomography (PET), magnetic resonance imaging, or invasive coronary angiography. Treatment includes antiangina therapy and control of CV risk factors. A related syndrome, MI with nonobstructive coronary arteries (MINOCA), is more common in younger patients. However, in contrast to MINOCA, type 2 MI is more common in older adults. Type 2 MIs also result from supply–demand mismatch in the absence of obstructed coronary arteries when physiologic stresses (e.g., tachycardia, anemia, infections, hypertension) overwhelm limited CV flow reserves.
Acute Coronary SyndromeS (ACS) (See Chapter 37 , Chapter 38 , Chapter 39 )
Epidemiology
In the United States, the average age at first acute MI is 65.6 years in men and 72.0 years in women. In men, the incidence of MI peaks in the 65 to 74 year age group and declines at older ages, whereas the incidence in women increases progressively with age, surpassing that in men after age 85. The prevalence of MI in men increases from 2.8% at ages 40 to 59 to 11.5% at ages 60 to 79 and to 17.3% after age 80; comparable figures for women are 2.1%, 4.2%, and 12.7%. About 60% of hospitalizations for ACS are in patients ≥65 years, with approximately 85% of ACS mortality occurring in this age group; 32% to 43% of non-ST elevation (NSTE)-ACS admissions and 24% to 28% of ST-elevation MI (STEMI) admissions are in patients ≥75 years. NSTE-ACS is far more prevalent than STEMI in the older population, as is type 2 MI.
Presentation
Older patients with ACS are less likely than younger patients to present with typical ischemic chest pain but more likely to experience dyspnea, diaphoresis, nausea and vomiting, presyncope or syncope, weakness, altered mental status, or confusion, even when chest discomfort is present. Chest pain is reported in only ∼40% of those >85 years compared with almost 80% in those <65 years, often leading to delays in diagnosis and initiation of therapy. Heart failure, pulmonary edema, AF, bradyarrhythmias, hypotension, and shock all occur more frequently in older patients with ACS than in younger individuals, in part reflecting the marked reduction in CV reserve inherit to the aging process.
Diagnosis
Because older patients often present with atypical symptoms and NSTE-ACS, a heightened index of suspicion for ACS is required. The ECG may be nondiagnostic due to prior MI, conduction abnormalities, or paced rhythm, but ischemic ST-T changes carry the same implications as in younger patients. Older individuals tend to have higher baseline levels of troponin (cTn), such that 20% of community-dwelling adults >70 years have levels above the 99th percentile, and baseline levels tend to be higher in men than in women. These factors should be considered in evaluating the clinical significance of slight cTn elevations in older patients. The emergence of high-sensitivity cTn (hs-cTn) could lead to over-diagnosis of ACS in older adults, with increased hospitalization and downstream testing, but additional data are needed.
Management
Older patients present complex challenges because of atypical symptomatology, high prevalence of cardiac and noncardiac comorbidities, age-related alterations in CV structure and physiology, and increased risk for adverse drug events and interactions due to polypharmacy. Although treatment standards for ACS do not differ with age, medication side effects, especially bleeding from antiplatelet and antithrombotic therapy, are more common in older patients.
Revascularization-STEMI
Timely reperfusion is the cornerstone of care for older patients with STEMI, with absolute benefits equal or greater than in younger patients given their higher mortality risks. However, older patients have more contraindications to reperfusion, and even if eligible are less likely to receive it. Primary PCI with stent placement is preferred over thrombolysis in older adults as it results in greater survival benefit, reduced reinfarction and need for repeat revascularization, and less intracranial hemorrhage. Fibrinolytic therapy has also been associated with an increased risk of myocardial rupture after age 75. If primary PCI cannot be performed within 120 minutes of symptom onset, fibrinolytic therapy is a reasonable option in carefully selected older patients with STEMI. In patients over age 75, streptokinase is associated with less intracranial bleeding than more fibrin-specific agents.
You're Reading a Preview
Become a Clinical Tree membership for Full access and enjoy Unlimited articles
If you are a member. Log in here
