Cardiovascular Disease

Arterial structure and function

Increased lumen size

Increased wall thickness (intimal-media thickening)

Increased calcification

Increased tortuosity of large vessels

Increased collagen cross-linking

Degeneration and fragmentation of elastin

Decreased endothelial function

Increased stiffness of large and medium-sized arteries (decreased distensibility)

Cardiac anatomy

Increased atrial size (LA > RA)

Increased LV wall mass and thickness

Increased LV stiffness (decreased compliance)

LV fibrosis and collagen accumulation

Degeneration (calcific) of valve leaflets and annulus

Decreased LV cavity size and longitudinal shortening

Fibrosis, calcification, and degeneration of conducting system

Decline in number of sinoatrial node pacemaker cells


Increase in systolic blood pressure

Increase in pulse wave velocity

Earlier reflection of pulse wave and augmentation of blood pressure in late systole

Decrease in aortic peak flow velocity

Reduction in peak LV filling rate

Decreased ratio of early LV filling (E) to atrial filling (A)

Changes during exercise

Decrease in maximum heart rate (220-age)

Decline in heart rate variability

Increase in atrial and ventricular ectopy

Reduced cardiac output reserve

Reduction in end systolic volume reserve

Reduction in VO2 Max

Impaired peripheral vasodilation

LA left atrium, RA right atrium, LV left ventricular/ventricle, A-V atrioventricular, VO 2 Max maximal oxygen consumption

21.3 Traditional Cardiovascular Risk Factors

21.3.1 Hypertension

Age-associated increased central arterial stiffness, increased peripheral resistance, and impaired vascular reactivity contributed to hypertension being the most prevalent risk factor for CVD in older adults [6]. By age 75, approximately 80 % of women and 70 % of men in the USA are classified as hypertensive, yet they have the lowest rates of optimal control [7, 8]. With vascular aging, the systolic blood pressure increases progressively, whereas the diastolic blood pressure peaks at approximately age 50 and then plateaus before declining after 60 years of age in both men and women. As a result, isolated systolic hypertension (ISH , defined as systolic blood pressure over 140 mmHg and diastolic blood pressure below 90 mmHg) is the dominant form of hypertension in older adults. In turn, ISH is strongly associated with an increased risk for stroke, end-stage renal disease, myocardial infarction (MI), heart failure, and CV and all-cause mortality. While the treatment of hypertension at any age (including the very elderly), reduces CV and cerebrovascular events (Table 21.2), optimal treatment thresholds and target blood pressures have not been clearly defined [9, 10].

Table 21.2
Clinical trials of hypertension in older adults


Risk reduction %







Australian [152]



33 %

18 %


31 %

EWPHE [153]



36 %

20 %

22 %

29 %

Coope [154]



42 %

−3 %

32 %

24 %

STOP_HTN [155]



47 %

13 %

51 %

40 %

MRC [156]



25 %

19 %


17 %

HDFP [157]



44 %

15 %


16 %

SHEP [158]



33 %

27 %

55 %

32 %

SYST-Eur [159]



42 %

26 %

36 %

31 %

STONE [160]



57 %

6 %

68 %

60 %

Syst-China [161]



38 %

33 %

38 %

37 %

HYVET [10]



30 %

28 %

64 %

34 %




11 %

12 %

33 %

25 %

CAD coronary artery disease, CHF congestive heart failure, CVA cerebrovascular accident, CVD cardiovascular disease, EWPHE European Working Party on High Blood Pressure in the Elderly, HDFP Hypertension Detection and Followup Program, MRC Medical Research Council, NR not reported, SHEP Systolic Hypertension in the Elderly Program, STONE Shanghai Trial of Nifedipine in the Elderly, STOP-HTN Swedish Trial in Old Patients with Hypertension, Syst-China Systolic Hypertension in China, Syst-Eur Systolic Hypertension in Europe

In the Hypertension in the Very Elderly Trial (HYVET) , 3845 patients 80 years of age or older (mean 83.6 years, 60.5 % women) with systolic blood pressure ≥160 mmHg were randomized to the diuretic indapamide 1.5 mg or matching placebo [10]. Perindopril or placebo was added as needed to achieve a target blood pressure <150/80 mmHg. The primary outcome was fatal or nonfatal stroke. After a mean follow-up of 1.8 years, active treatment was associated with a 30 % reduction in the primary outcome, and reductions in secondary outcomes of incident heart failure and all-cause mortality. The results of HYVET led to a recommendation by several hypertension guideline committees to aim for a goal of <150 mmHg when treating systolic hypertension in patients ≥80 years of age.

More recently, the Systolic Blood Pressure Intervention Trial (SPRINT) randomized 9361 patients ≥50 years of age (28.2 % ≥75 years of age) at increased cardiovascular risk (as defined by subclinical or clinical CVD, chronic kidney disease, 10-year risk of CVD ≥15 % based on the Framingham Risk Score, and/or age ≥75 years) and with baseline systolic blood pressure 130–180 mmHg to intensive treatment (target blood pressure <120 mmHg) or standard treatment (target blood pressure <140 mmHg) [11]. Patients with diabetes mellitus, symptomatic heart failure in the preceding 6 months, recent acute coronary syndrome (ACS) , prior stroke, orthostatic systolic blood pressure <110 mmHg, unintentional weight loss (a component of frailty), or residence in a nursing home or assisted living facility were excluded. Women and patients with multimorbidity were also under-represented. The primary outcome was a composite of myocardial infarction (MI), other ACS, stroke, heart failure, or cardiovascular death. The study was stopped prematurely at a median follow-up of 3.26 years due to a significant benefit of intensive treatment on the primary outcome (2.19 % per year with standard treatment vs. 1.65 % per year with intensive treatment, hazard ratio 0.75, 95 % CI 0.69–0.89, p < 0.001). Outcomes were similar in patients ≥75 years of age compared to those <75 years but the absolute benefit was numerically greater in the older subgroup. All-cause mortality, CV mortality, and incident heart failure were significantly reduced with intensive treatment, but there was no effect on MI, ACS, or stroke. The number needed to treat for 1 year to prevent one primary outcome event was 185. The mean number of blood pressure medications was 1.8 in the standard treatment group and 2.8 in the intensive treatment group. Serious adverse events, including acute kidney injury, electrolyte abnormalities, hypotension, and syncope (but not injurious falls) were all significantly more frequent in the intensive therapy group. Annual rates of serious adverse events attributed to anti-hypertensive treatment were 1.44 % in the intensive therapy group and 0.77 % in the standard therapy group (number needed to harm 149). The incidence of adverse events was similar among patients older or younger than age 75. The effects of intensive treatment on quality of life and cognitive function have not yet been reported.

The implications of SPRINT for treatment of older adults with hypertension are uncertain, as the modest absolute benefit with respect to major CV events and death must be balanced against the potential for adverse events, increased burden of medications, and unknown impact on quality of life, functional status, and cognition. In addition, a substantial proportion of older adults would not have met the SPRINT inclusion/exclusion criteria, and the applicability of the findings to these individuals is unknown. Based on the results of HYVET and current guidelines, it is reasonable to treat individuals ≥75 years of age who are suitable candidates for anti-hypertensive drug therapy to a target systolic blood pressure of <140 mmHg (age 75–79 years) or <150 mmHg (age ≥80 years). More aggressive treatment should be individualized based on the clinical profile and patient preferences.

Management of hypertension in older adults is often complicated by orthostatic or post-prandial hypotension [12], which may be associated with light-headedness and increased risk for falls and syncope. In addition, “white coat” hypertension is common in older adults (i.e., office blood pressure higher than home blood pressure), and older individuals with stiff arteries may exhibit pseudohypertension (blood pressure measured by sphygmomanometer higher than central aortic pressure) [13, 14]. For these reasons, it is important to measure blood pressure in the sitting and standing positions and, when feasible, to obtain blood pressure readings in the home environment [12]. In some cases, 24-hour ambulatory blood pressure monitoring may be helpful in determining the presence and severity of hypertension, as well as the variability in blood pressure readings [15]. In patients with significant orthostatic hypotension (decline in systolic blood pressure ≥20 mmHg on standing), titration of anti-hypertensive therapy should be very gradual and should include periodic assessments of orthostatic blood pressure changes and evaluation for symptoms attributable to orthostasis.

21.3.2 Hyperlipidemia

Dyslipidemia remains an important risk factor for CVD in older adults up to age 85; after age 85, the association of lipid levels with CVD is less clear [1618]. In addition, the strength of association between cholesterol levels and CVD declines with age, such that total cholesterol and LDL cholesterol become less predictive of CV events at older age. Factors affecting the relationship between cholesterol and CVD risk at increased age include survival bias among individuals with low CVD risk despite increased cholesterol levels, and the impact of co-existing diseases (e.g., malignancy, chronic inflammatory disorders) and malnutrition (a common condition in older adults). Statins are highly efficacious for the treatment of dyslipidemia, and numerous trials have documented the benefits of statins on CVD outcomes [1922]. However, few patients over age 80 have been enrolled in these trials, and patients with complex comorbidity have been excluded. In addition, statin side effects, such as myalgias, may be more common in older adults, and there is weak evidence that statins may be associated with cognitive impairment in some individuals. Recognizing the paucity of evidence on statins in older patients, current guidelines recommend that treatment decisions consider anticipated benefits and adverse effects (including their time horizon), life expectancy, comorbidities, and individual treatment priorities [23]. In addition, the guidelines advise caution in using high intensity statin therapy in individuals over 75 years of age.

21.3.3 Diabetes Mellitus

Diabetes mellitus (DM) is a powerful and independent predictor of the development and progression of CVD in older adults, imparting an increase in relative risk of CAD of 1.4 in men and 2.1 in women 65 and older with a significant sex interaction (i.e., stronger association in women) [24]. Although the relative risk in individuals over the age of 65 is lower than in younger individuals with DM, the high prevalence of DM in older adults results in greater excess risk [25].

Management of CV risk in patients with DM should focus on treating co-existing CVD risk factors, including hypertension and dyslipidemia, which are present in 71 and 65 % of older diabetics, respectively [21]. Additionally, utilization of an angiotensin-converting enzyme inhibitor (ACE-I) in older adults with diabetes is effective for reducing CV mortality [26]. Regular physical activity and maintaining a healthy body weight should be encouraged. Additional recommendations for managing DM in older adults are provided in Chap. 23.

21.3.4 Smoking

Smoking accounts for 30 % of the attributable risk of all strokes and 36 % of first acute coronary events [27]. In older adults the prevalence of smoking decreases but it still remains a significant risk factor. Although the relative risk for MI or death as a result of smoking in an individual over the age of 70 is twice that of an individual age 55–60, older patients are less likely to receive smoking cessation counselling or interventions [28].

Individuals who smoke should be advised of the risks associated with smoking and given guidance on cessation strategies. Elderly individuals may be resistant to changing life-long habits, but the negative effects of continued smoking irrespective of age demand continued efforts to promote smoking cessation.

21.4 Geriatric Syndromes and Cardiovascular Disease

21.4.1 Multimorbidity

Multimorbidity , defined as the presence of 2 or more chronic conditions, increases exponentially with age and is present in over 70 % of individuals 75 years or older [29]. By the age of 65, more than 60 % of individuals have 2 or more chronic conditions, >25 % have 4 or more chronic conditions, and nearly 10 % have 6 or more conditions; by age 85, >50 % of individuals have 4 or more chronic conditions and 25 % have 6 or more conditions. The accumulation of chronic conditions culminates in a vastly heterogeneous population of older adults for whom balancing the management of multiple medical problems becomes paramount.

Among Medicare beneficiaries with CVD, the burden of multimorbidity is substantial; for example, over 50 % of individuals with a diagnosis of heart failure or stroke have 5 or more co-existing chronic medical conditions [29]. In older adults with CVD, the most common concomitant non-CVD conditions are arthritis, anemia, and diabetes mellitus, with prevalence rates ranging from 40 to 50 %. Other common conditions include chronic kidney disease, cognitive impairment, chronic obstructive lung disease, and depression, each of which much be considered when developing individual treatment strategies for the management of CVD [30].

21.4.2 Polypharmacy and Drug Interactions

Older adults with multimorbidity are frequently seen by numerous general and specialist providers which can result in competing management strategies and numerous prescriptions for medications. Polypharmacy , often defined as concomitant use of five or more medications, is associated with markedly increased risk for drug–drug interactions, drug–disease interactions, and therapeutic competition (the recommended treatment for one condition may adversely affect and/or compete with another co-existing condition) [31]. Approximately 50 % of older adults are taking at least one medication with no active indication, and many of these drugs are initiated during hospitalization, such as stress ulcer prophylaxis and antipsychotics for delirium [32]. Careful medication reconciliation including prescribed medicines, over the counter pharmaceuticals, and herbal therapies should be performed at each provider interaction. Adverse consequences of polypharmacy including poor adherence, adverse drug events, hospitalization, and mortality are related not only to the number of medications but also to the regimen complexity, so attention should be given to limiting the number of medications as well as simplifying the dosing schedule [3234].

Non-steroidal anti-inflammatory drugs (NSAIDs) are frequently taken by older adults to relieve burdensome pain or for treatment of arthritis. However, NSAIDs, including the cyclo-oxygenase 2 (COX-2) inhibitors , increase the risk of atherothrombotic vascular events and incident heart failure [35]. In addition, NSAIDs have adverse interactions with many CV medications, including diuretics, other anti-hypertensive agents, and antithrombotic drugs. NSAIDs have also been associated with worsening renal function and increased risk for gastrointestinal bleeding. For these reasons, the FDA and the American Heart Association suggest minimizing the use of NSAIDs when feasible, and using the lowest possible doses for the shortest period of time [36]. Polypharmacy and medication management are discussed in greater detail in Chap. 5.

21.4.3 Cognitive Impairment

Approximately 13 % of community dwelling adults over the age of 65 have a diagnosis of dementia. However, the total burden of disease is likely to be much higher due to under-recognition of dementia by patients, families, and health care providers, particularly in the early stages [37, 38]. In people over the age of 80, the prevalence of dementia increases to 40 %, and in advanced heart failure patients, 30–60 % have comorbid dementia [39, 40]. Older individuals with CVD also have a high prevalence of mild cognitive impairment (the prodromal phase of dementia) as compared to individuals without CVD, and patients with cognitive impairment and CVD have worse outcomes than those with CVD alone. Older adults with heart failure have a twofold increased risk of impaired cognition, including deficits in attention, executive function, and episodic memory, and these impairments tend to be more pronounced during episodes of decompensation [41]. Executive dysfunction, in particular, can reduce the ability to adhere to recommended therapies and participate in disease management programs [42]. In part for these reasons, the presence of cognitive impairment increases cost, management complexity, and mortality rates in older adults with CVD. Diagnosis and management of dementia are discussed in Chap. 4.

21.4.4 Frailty

Frailty is a geriatric syndrome that represents an accelerated path of biological decline across multiple interrelated organ systems and a loss of homeostatic reserve in response to stressors [43]. Although different criteria for frailty have been proposed, the frailty phenotype originally described in the Cardiovascular Health Study comprises unintentional weight loss, exhaustion, weakness, slowness, and low physical activity (pre-frail: 1–2 criteria; frail: ≥3 criteria) [43]. More recently, cognitive impairment has emerged as an additional component of frailty [44]. The estimated prevalence of frailty in community cohorts is 7 % but increases to 20 % in individuals over age 80. In older patients hospitalized with CVD, especially heart failure, it is estimated that frailty rates approach 50 % [45]. Frailty is associated with an increased risk of adverse outcomes including falls, functional decline, disability, institutionalization, and death [43, 46, 47]. A bidirectional relationship exists between frailty and CVD such that frailty is an independent predictor of the development and progression of a wide range of CV disorders [48]. Conversely, the presence of CVD increases the risk of frailty, and older adults with concomitant frailty and CVD have significantly worse outcomes than those with CVD alone (hazard ratios ranges from 2 to 4 depending on the specific disease). Chapter 1 provides a comprehensive discussion of the recognition and management of frailty.

21.4.5 Comprehensive Geriatric Evaluation

Although disease-focused evaluation of symptoms may facilitate assessment of the primary CV diagnosis, it does not allow for a more comprehensive evaluation of the multitude of factors that may impact optimal management. Implementing a more patient-centered approach to prioritizing goals of care within the context of co-existing multimorbidity, geriatric syndromes, cognitive impairment, and social and psychological factors can result in a management strategy better aligned with patient preferences. Table 21.3 provides an overview of commonly used tools for assessment of geriatric patients. The reader is also referred to Chap. 8 for practical guidance on office based geriatric assessment.

Table 21.3
Screening tools for common geriatric conditions

Geriatric condition

Assessment tool


Fried frailty scale: grip strength, gait speed, exhaustion, weight loss, and physical activity questionnaire [43]

Short physical performance battery [162]

Rockwood frailty index

Functional status

Katz activities of daily living [163]

Lawton instrumental activities of daily living [164]

Timed up and go [165]

Functional reach [166]


Montreal cognitive assessment (www.​mocatest.​org)

Mini-Cog [167]

Mini mental state examination (MMSE)

Weight loss/Sarcopenia

Grip strength

Body mass index or weight change, 3–5 % decline [43, 168, 169] annually


Geriatric depression scale [170]

Patient health questionnaire-9 [171]

21.5 Cardiovascular Diseases Common in Older Adults

21.5.1 Coronary Artery Disease

While chest pain or discomfort is the most common presenting symptom in patients of all ages with coronary artery disease (CAD ), dyspnea is frequently the presenting symptom in older adults and women, particularly in the presence of multimorbidity. Atypical or non-specific symptoms are also common in older adults with CAD and may include weakness, confusion, decline in functional status, reduced physical activity, nausea, and loss of appetite. For these reasons, a high clinical suspicion for CAD in older adults should be maintained (especially the very elderly). Older adults may also be less likely to recognize or report symptoms of CAD due to reduced physical activity or cognitive impairment. Further, older adults may minimize symptoms owing to fear of possible interventions, hospitalization, and loss of independence.

21.5.2 Acute Myocardial Infarction

Ischemic heart disease is the leading cause of mortality in both men and women in the USA, with nearly 85 % of deaths occurring in individuals 65 years and older and over 50 % in those 75 and older [49, 50]. The high prevalence of ischemic heart disease in older adults contributes to the increased number of deaths, but greater in-hospital and 6-month mortality rates are also a significant factor.

A critical step in optimum management of older adults with acute myocardial infarction (AMI) is prompt diagnosis and re-vascularization, if appropriate, but such treatment is contingent upon recognition of symptoms and the presence of diagnostic electrocardiographic (ECG) changes . In the Global Registry of Acute Coronary Events (GRACE), almost 50 % of participants >85 years with an ACS presented with dyspnea rather than chest pain [51]. In the Framingham cohort, silent or unrecognized infarcts accounted for almost 60 % of all MIs in individuals over age 85 [52]. Current practice guidelines recommend that an ECG should be obtained and reviewed within 10 min of presentation in individuals with symptoms consistent with ACS. In older adults, particularly women, the time to first ECG is considerably longer than in younger patients and it is more likely to be non-diagnostic [52]. The higher prevalence of non-specific symptoms, pre-existing ECG abnormalities, and non-ST segment elevation MI (NSTEMI) in elderly patients can further delay treatment initiation.

Reperfusion therapy in the form of fibrinolysis or more commonly primary percutaneous coronary intervention (PCI) in ST-elevation MI (STEMI) is associated with reduced in-hospital mortality, subsequent heart failure, and long-term morbidity and mortality [53, 54]. Despite a greater incremental benefit obtained by elderly patients, they are less likely to receive reperfusion therapy [55]. In the Myocardial Infarction National Audit Project (MINAP) , only 55 % of patients ≥85 presenting with STEMI received reperfusion therapy as compared to 84 % of patients age 65 or younger. Primary PCI is the treatment of choice if performed within 90 min of arrival to the hospital and within 12 h of onset of symptoms. [56] Increased actual and perceived risks in older adults undergoing PCI likely contribute to lower utilization rates. Antiplatelet Therapy

In the second International Study of Infarct Survival-2 (ISIS-2) [57], early aspirin therapy in patients with STEMI reduced 35-day mortality by 23 % overall with corresponding effects in individuals over the age of 70. Chronic aspirin therapy following MI also decreases recurrent MI, stroke, and all-cause mortality irrespective of age. Clopidogrel in addition to aspirin reduces recurrent MI and death in the 12 months following hospital admission for ACS, whether or not PCI is performed [58, 59]. Table 21.4 summarizes clinical trials of antiplatelet agents in the treatment of ACS, including outcomes and caveats for older adults. Older adults are at increased risk for bleeding complications associated with all antiplatelet agents, including aspirin, and the use of dual antiplatelet therapy (e.g., aspirin with clopidogrel) and especially triple therapy (2 antiplatelet agents and an anticoagulant) further increases risk. Compared to clopidogrel, prasugrel is associated with increased risk of intracranial hemorrhage in patients ≥75 years of age and is not recommended for use in that age group except in patients at high risk for stent thrombosis [60]. Similarly, vorapaxar is associated with significantly higher risk of bleeding in patients over age 75 [61].

Table 21.4
Antiplatelet therapy for use in acute coronary syndromes or coronary artery disease

Triala (sample size)

Intervention vs control


Age (years)

Bleeding risk

Precautions/Geriatric considerations (per Lexicomp®)

Irreversible cyclo-oxygenase inhibitors


ISIS-2 [57]

N = 17,187

Aspirin (162.5 mg)



35 day CV mortality:

• 9.4 % in aspirin group versus 11.8 % in Placebo group

• 23 % reduction in odds of primary outcome in the aspirin group compared with placebo

• Outcome % by age:

<60 years: 4.5 % in aspirin group versus 5.5 % in Placebo group

60–69 years: 10.9 % in aspirin group versus 14.0 % in Placebo group

≥70 years: 17.6 % in aspirin group versus 22.3 % in Placebo group

<60 = 45 %

60–69 = 35 %

≥70 = 20 %

(Aspirin group)

Major bleeding:

• 0.4 % in Both groups

• Risk for peptic ulcers and/or hemorrhage

• CNS adverse effects in elderly even with low doses

• >325 mg Potentially inappropriate according to BEERS criteria
M-HEART II [172]

N = 752

Aspirin 325 daily


Sulotroban 800 mg four times daily



6 h before planned percutaneous transluminal coronary angioplasty

Death, myocardial infarction, or clinically important restenosis at 6 months:

• 30 % in Aspirin group versus 41 % in Placebo group

• OR 0.63 (p = 0.05) compared to placebo

Mean in Aspirin group = 58 (±10)

Adenosine diphosphate (ADP P2Y 12 ) receptor inhibitors


CURE [59]

N = 12,562

Clopidogrel 300 mg loading dose + 75 mg daily



(In addition to Aspirin in both groups)

Composite of death from CV causes, nonfatal MI or stroke:

• 9.3 % in Clopidogrel group versus 11.4 % in Placebo group

• RR 0.8 (p < 0.001)

• Outcome % by age:

≤65 years: 5.4 % in Clopidogrel group versus 7.6 % in Placebo group

+>65 years: 13.3 % in Clopidogrel group versus 15.3 % in Placebo group

Mean in Clopidogrel group = 64.2 (±11.3)

Major bleeding:

• 3.7 % in Clopidogrel group versus 2.7 % in Placebo group

• RR 1.38 (p = 0.001)

• Plasma concentrations of the main metabolite were significantly higher in the elderly (≥75 years)

• Use with caution in hepatic or renal impairment

N = 2658

Clopidogrel 300 mg loading dose



(In both groups Aspirin 75–325 mg and PCI after randomization)

Composite of CV death, MI, or urgent target-vessel revascularization within 30 days of PCI:

• 8.8 % in clopidogrel group versus 12.6 % in Placebo group

• RR 0.69 (95 %CI 0.54–0.87)

• Outcome % and RR by age:

 ≥65 years: 13.4 % in Aspirin group versus 16.9 % in Placebo group

And RR 0.79 (95 % CI 0.57–1.08)

 <65 years: 5.9 % in Aspirin group versus 9.8 % in Placebo group

And RR 0.59 (95 % CI 0.41–0.84)

Mean in Clopidogrel group = 61.6 (±11.2)

Major bleeding:

PCI to 30days-

• 1.6 % in Clopidogrel group versus 1.4 % in Placebo group

• RR 1.13 (p = 0.69)

PCI to follow up (8 months)-

• 2.7 % in Clopidogrel group versus 2.5 % in Placebo group

• RR 1.12 (p = 0.64)

N = 9478

Clopidogrel 75 mg + Aspirin (75–162 mg) daily


Placebo + Aspirin (75–162 mg) daily

CV death (including hemorrhagic death), MI, or stroke (from any cause):

• 7.3 % in Clopidogrel group versus 8.8 % in Placebo group

• HR 0.83 (p = 0.010)

Median = 64

IQR = 56–71

Severe bleeding:

• 1.7 % in Clopidogrel group versus 1.5 % in Placebo group

• HR 1.1 (p = 0.51)



N = 13,608

Prasugrel 60 mg loading dose


Clopidogrel 300 mg loading dose

Composite rate of CV mortality, nonfatal MI, or nonfatal stroke:

• 9.9 % in Prasugrel group versus 12.1 % in Clopidogrel group

• 0.81 HR p < 0.001

Median = 61

IQR = 53–69

Major bleeding:

• 2.4 % in Prasugrel group versus 1.8 % in Clopidogrel group

• HR 1.32 (p = 0.03)

• Not recommended for use in elderly ≥75 years unless high cardiac risk due to risk of fatal intracranial bleeding and lack of certain benefit in this age group

• AUC of the active metabolite was 19 % higher in ≥75 years of age

Tricagrelor (Brilinta)

PLATO [61]

N = 18,624

Tricagrelor 180 mg loading dose, 90 mg twice daily


Clopidogrel 300 mg loading dose with 75 mg daily

Composite of CV mortality, MI, or stroke at 12 months:

• 9.8 % in Ticagrelor group versus 11.7 % in Clopidogrel group

• 0.84 HR p <0.001

Median = 62

43 % of the participants were ≥65 years and 15 % were ≥75 years of age


• 11.6 % in Ticagrelor group versus 11.2 % in Clopidogrel group (p = 0.43)

• Avoid use in severe hepatic impairment

• Caution in renal impairment, hyperuricemia, or gouty arthritis

Proteaseactivated receptor1 (PAR1) antagonists


TRACER [174]

N = 12,944

Vorapaxar 40 mg loading dose 2.5 mg daily


Placebo with stratification (intention to use a glycoprotein IIb/IIIa inhibitor (vs. none) and parenteral direct thrombin inhibitor (vs. other antithrombinagents)

Composite of CV mortality, MI, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization at 2 years:

• 18.5 % in Voraxapar group versus 19.9 % in Placebo group

• HR 0.92 (p = 0.07)

Median =64

IQR = 58–72

≥75 = 16.9 %

Moderate and severe BLEEDING (GUSTO) 2 years:

• 7.2 % in Voraxapar group versus 5.2 % in Placebo group

• HR 1.35 (p < 0.001)

• Moderate/severe bleeding was much higher for vorapaxar in the ≥74 year quintile at 13 % vs 8.4 % with placebo

Glycoprotein IIB/IIIA inhibitors (IV use only)



N = 7800

Abciximab 24 h or 48 h (0.25 mg/kg bolus followed by a 0.125 μg/kg per min maxi of 10 μg/min



(all receive aspirin)

30-day death from any cause or MI

24 h:

• 8.2 % in Abciximab group with OR 1 (95 % CI 0 · 83–1 · 24)

48 h:

• 9.1 % in Abciximab group with OR 1.1 (95 % CI 0 · 94–1 · 39)


8 % in Placebo group

Mean = 65 (±11)

Major bleeding requiring blood transfusion:

24 h: Abciximab—2 %

48 h: Abciximab—3 % (p < 0.05)


2 % in placebo

• Use with caution in patients >65 years and <75 kg = due to increased risk of bleeding



N = 10,948

Eptifibatide Bolus dose of 180 μg/kg + infusion of 1.3 μg/kg/min, or bolus dose of 180 μg/kg + infusion of 2 μg/kg/min



30-day death from any cause or MI:

• 14.2 % in Eptifibatide versus 15.7 % in Placebo

• 1.5 % absolute reduction (p = 0.04)

• Odds ratio closer to null for more than 65 year olds

Median = 64

IQR = 55–71

Major (TIMI):

• 10.6 % in Eptifibatide versus 9.1 % in Placebo (p = 0.02)

• Dose reduction for renal impairment (CrCl <50 ml/min)

Increased bleeding risk in older patients and <70 kg



N = 2139

Tirofiban Bolus 10 μg/kg


Placebo over a 3-minute period

Composite end point (mortality, MI, CABG recurrent surgical or interventional revascularization of target vessel or ischemia) at 30 days:

• 10.3 % in Tirofiban group versus 12.2 % in Placebo group

• 16 % relative reduction (p = 0.160)

Mean = 59.2

Major bleeding:

• 5.3 % in Tirofiban group versus 3.7 % in Placebo group

(p = 0.096)

• Elderly patients receiving tirofiban with heparin or heparin alone had a higher incidence of bleeding

CV cardiovascular, MI myocardial infarction, HR hazard ratio, OR odds ratio, RR relative risk, IQR interquartile range

aTrial acronyms: ISIS-2 The Second International Study of Infarct Survival, M-HEART II Multi Hospital Eastern Atlantic Restenosis Trial; CURE Clopidogrel in Unstable angina to prevent Recurrent Events; PCI CURE Percutaneous Coronary Intervention Clopidogrel in Unstable angina to prevent Recurrent Events, CHARISMA Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance; TRITON-TIMI Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction, PLATO The Study of Platelet Inhibition and Patient Outcomes, TACER Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome, GUSTO-IV ACS glycoprotein IIb/IIIa receptor blocker abciximab on outcome in patients with acute coronary syndromes, PURSUIT Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy; RESTORE Randomized Efficacy Study of Tirofiban for Outcomes and REstenosis Antithrombotic Therapy

Activation of thrombin plays an important role in the pathway of ACS and blockade of thrombin by heparin is a recommended therapy. Unfractionated heparin is associated with higher rates of bleeding in older adults as a result of low protein binding and impaired renal function [62]. If appropriate, low molecular weight heparin (LMWH) provides a more reliable therapeutic effect and has been shown to reduce recurrent angina, MI, and death [63]. However, LMWH should be used with caution in patients with stage IV-V chronic kidney disease (est. creatinine clearance <30 cc/min).

Following a large anterior MI, the risk of apical LV thrombosis warrants treatment with warfarin for at least 3 months to reduce thromboembolic events [64]. As noted above, the risk of bleeding on triple antithrombotic therapy is increased in older adults, and this factor should be carefully considered in therapeutic decision-making [65]. As a general principle, intensive antithrombotic therapy should be continued for as short a duration as clinically warranted, especially in patients at high risk for bleeding complications. Secondary Prevention

In addition to aspirin, oral beta-blockers reduce recurrent events and mortality irrespective of age in both the acute phase and during long-term follow-up after ACS [6668]. Risk factors for drug–disease interactions with beta-blockers (i.e., bradycardia, hypotension, exacerbation of acute heart failure) are more common in older adults but should not preclude administration of these medications; close observation and careful titration are recommended [69].

Angiotensin-converting enzyme inhibitors (ACE-I) are beneficial in older adults following AMI, particularly in the setting of LV dysfunction and heart failure. ACE-I therapy initiated in the hospital and continuing after discharge reduces mortality, hospitalizations, and the progression of LV dysfunction [70, 71]. Angiotensin receptor blockers (ARBs) , including losartan and valsartan, have comparable effects to ACE-I and are appropriate second line agents when ACE-I are not tolerated due to cough [72, 73]. Combination treatment with an ACE-I and ARB does not reduce mortality but increases risk of adverse drug events.

21.5.3 Stable Coronary Artery Disease

The management of chronic CAD with or without antecedent MI focuses on optimum risk factor modification and symptom control. As a result of vascular aging and accumulation of risk factors, CAD in older adults tends to affect multiple arteries and to be more diffuse and more severe than in younger adults. Diagnostic stress testing is indicated in older adults to investigate suspected CAD but baseline ECG abnormalities warrant concomitant imaging (echo, magnetic resonance imaging, or nuclear perfusion) to improve accuracy. Physical limitations may restrict the use of exercise stress testing but pharmacological stress testing (e.g., adenosine, regadenoson or dobutamine) provides a suitable alternative. Coronary computed tomographic angiography (CTA) is an alternative to stress imaging in selected cases; a limitation of this technique is the need for intravenous contrast administration and potential risk for acute kidney injury. Coronary angiography is appropriate in selected older patients with markedly abnormal stress test findings and/or limiting symptoms that do not respond adequately to medical therapy.

Management of stable CAD is designed to alleviate symptoms, improve quality of life, and reduce the risk of adverse ischemic events. First line anti-anginal therapy should include a beta-blocker if tolerated. Alternative medications include calcium channel blockers, nitrates and ranolazine. Side effects from beta-blockers and calcium channel blockers are more common in older adults and may include fatigue, weakness, and loss of energy, constipation, dizziness, low blood pressure, lower extremity swelling, and depressive symptoms.

Elective PCI for the management of stable angina symptoms is an alternative treatment strategy and may be beneficial in individuals intolerant of optimal medical therapy or in those who remain symptomatic despite medications. Although PCI is effective in reducing symptoms, data from the COURAGE trial indicate that routine PCI in patients with chronic stable CAD does not reduce mortality or risk of MI compared to optimal medical therapy alone (including aggressive CV risk reduction) [74]. The findings of COURAGE were similar in patients younger or older than 65 years.

In appropriately selected patients, coronary artery-bypass grafting (CABG) reduces symptoms and improves quality of life. In high risk individuals, CABG also confers a mortality benefit [75]. Older patients undergoing CABG are more likely than younger patients to have multimorbidity, cognitive impairment, reduced functional status, and more advanced and diffuse CAD [76]. As a result, perioperative morbidity and mortality are higher, with higher rates of respiratory failure, bleeding, acute kidney injury, atrial fibrillation, heart failure, and delirium. In addition, postoperative cognitive impairment is more common in elderly individuals. For additional information on cardiothoracic surgery, see Chap. 10.

21.5.4 Heart Failure

Heart failure is primarily a disorder of older adults in part because CV aging, especially increased vascular and myocardial stiffness, increases vulnerability for developing heart failure [77]. In addition, heart failure is the “final common pathway” for nearly all CV disorders afflicting older adults. Heart failure affects 5.7 million Americans with approximately 870,000 new cases annually in individuals ≥55 years. It is the most common cause of hospital admission in individuals >65 years of age and is responsible for an estimated 1 million hospital discharges as primary diagnosis each year at a cost of approximately $30 billion in 2012 [78]. Heart failure contributes to more than 250,000 deaths annually in the USA, of which >85 % are in individuals over the age of 65. Mortality rates in advanced heart failure approach those of metastatic lung cancer; however, these poor outcomes are infrequently communicated to and comprehended by patients and families. Not only does heart failure account for significant adverse health outcomes, it has a major impact on quality of life, disability, and independence in elderly patients. See Chap. 6 for further discussion of palliative and end-of-life care in advanced heart failure.

Dyspnea on exertion, reduced exercise tolerance, orthopnea, lower extremity and abdominal swelling, and general fatigue are characteristic symptoms in both young and older adults with heart failure. Reduced baseline physical activity in older adults due to disability or sedentary life style can mask exertional symptoms. In contrast, non-specific symptoms including confusion, reductions in physical activity and functional status, nausea and loss of appetite are more common expressions of heart failure in elderly patients.

The goals of heart failure management in older adults should focus on reduction of symptom severity, improving quality of life, maintenance of functional status and independence, avoidance of hospitalization and institutionalization, and extending life in alignment with patient-centered goals. An interprofessional team approach to care is critical and should incorporate cardiovascular, non-cardiovascular, and social factors. Studies have shown that team care reduces readmissions and improves quality of life in older patients with heart failure . However, recent data indicate that up to two-thirds of readmissions are due to causes other than heart failure, which underscores the need to individualize care and to address prevalent comorbidities [79]. Medical Therapy

The mainstay of treatment for heart failure with reduced ejection fraction (HFrEF) includes beta-blockers, ACE-I or ARBs, diuretics, and mineralocorticoid antagonists. In addition, digoxin and vasodilators can be beneficial in selected cases. During long-term use beta-blockers improve LV systolic function and reduce hospital admissions and mortality [80, 81]. These effects are evident for all stages of heart failure and across all age groups, including beneficial effects in the elderly. Beta-blockers shown to be effective in clinical trials and approved for use in the USA for treatment of heart failure include metoprolol succinate and carvedilol. Bisoprolol and nebivolol have also demonstrated improved outcomes in heart failure patients but are not FDA approved for that indication [82, 83]. As with use in coronary artery disease, side effects and adverse events are more common in older adults; hence, it is appropriate to start with low doses, titrate gradually, and monitor closely.

ACE-I have favorable effects on left ventricular remodeling and are beneficial in patients with HFrEF irrespective of symptoms [8486]. However, since most landmark ACE-I trials included low numbers of elderly patients, the benefits of these agents in patients over 75–80 years of age are less well established. Nonetheless, ACE-I for HFrEF carry a class I indication regardless of age [42]. ARBs are a suitable alternative in the setting of ACE-I intolerance and benefits of ARBs have been shown in both young and older adults [87, 88]. ACE-I and ARBs are generally well tolerated but should be started at lower doses in older adults and titrated slowly while monitoring closely for hypotension, renal dysfunction, and electrolyte abnormalities (especially hyperkalemia).

Mineralocorticoid receptor antagonists (aldosterone receptor antagonists), including spironolactone and eplerenone, reduce mortality in patients with New York Heart Association (NYHA) class II-IV HFrEF and are recommended in these patients unless contraindicated [89, 90]. Patients with NYHA class II heart failure should have a history of prior CV hospitalization or elevated plasma natriuretic peptide levels to be considered for mineralocorticoid receptor antagonists [42]. Mineralocorticoid receptor antagonists are not recommended if the estimated glomerular filtration rate (eGFR) is <30 mL/min/M2 or if the serum potassium level is >5 meq/L. Adverse effects include hyperkalemia, especially in the setting of chronic kidney disease, but with close observation severe hyperkalemia is uncommon.

Diuretics , in combination with sodium restriction, are essential for treating acute decompensation and for maintaining euvolemia in the outpatient setting. In elderly patients, management of fluid and sodium balance must be considered in the context of social support, as well as functional and physical limitations. Titrating diuretic therapy according to daily weights and close monitoring of daily sodium and fluid intake may not be feasible in older adults with limited social support or significant functional, physical, or cognitive impairments.

Digoxin reduces heart failure symptoms and heart failure admissions in patients with HFrEF [91]. However, digoxin has no effect on mortality and it has a low therapeutic index with relatively high potential for serious adverse events, especially in older patients with reduced renal function. In older adults with preserved renal function (est. GFR ≥60 cc/min) digoxin may be useful as an adjunctive agent in patients who remain symptomatic despite standard therapy [92]. In such cases, low doses (e.g., 0.125 mg daily or every other day) should be utilized and levels should be monitored periodically, targeting a therapeutic range of 0.5–0.9 ng/ml [93].

The vasodilators hydralazine and isosorbide dinitrate are indicated in African American patients with moderate to severe heart failure symptoms, and they may also be useful in patients who are unable to take ACE-I or ARBs due to renal insufficiency or side effects [94, 95]. Limitations of these medications in older adults include the relatively high side effect profile and thrice daily dosing, which impacts the complexity of the regimen and may reduce medication adherence. Implantable Cardioverter-Defibrillators and Cardiac Resynchronization Therapy

Despite optimal medical therapy, patients with HFrEF are at an increased risk for sudden cardiac death due to ventricular arrhythmias. Implantable cardioverter-defibrillators (ICDs) reduce CV and all-cause mortality in selected patients and are recommended for individuals with irreversible heart failure (ischemic or non-ischemic), an LV ejection fraction ≤35 %, NYHA class II-III heart failure symptoms, and a life expectancy of at least 1 year [96, 97]. In the USA, >40 % of ICDs are implanted in patients over age 70 and 10–12 % are implanted in individuals over the age of 80. However, the majority of trials for primary and secondary prevention of sudden cardiac death with ICDs did not enroll patients over the age of 80 [98], and data from clinical trials and observational studies indicate that the mortality benefit of ICDs declines with age, primarily due to competing risks of death. For these reasons, the decision to implant an ICD in an older adult must be considered carefully and should include an estimation of the individual’s likely benefit in the context of other medical problems. In addition, shared decision-making to ensure alignment with the patients’ preferences and goals is essential. For example, frail individuals with recurrent hospital admissions are unlikely to benefit from an ICD. On the other hand, older adults who are otherwise suitable candidates should not be denied an ICD based solely on age. However, prior to implanting a device there should be a discussion about the potential for recurrent shock therapies and associated post-traumatic stress and anxiety, as well as options and preferences for disabling the device in the setting of terminal illness.

Cardiac resynchronization therapy (CRT) aims to improve hemodynamic parameters associated with impaired left ventricular function resulting from dyssynchronous LV contraction. In patients with HFrEF, a prolonged QRS duration (≥120 ms), and class II-IV symptoms, CRT has demonstrated improvements in symptoms, quality of life, and survival [99, 100]. Patients with left bundle branch block and QRS duration ≥150 ms are most likely to benefit, and there is evidence that women derive greater benefit than men. Although patients over the age of 80 were excluded from most of the randomized CRT trials, observational studies suggest that appropriately selected older adults often experience improved symptoms and quality of life. Therefore, CRT should be offered as an option in the management of advanced heart failure in older adults who are suitable candidates for the device. Heart Transplant and Advanced Heart Failure Devices

Although there is no widely accepted upper age limit for heart transplantation, most transplant centers use a cut-off of either 70 or 75 years. Among patients 65–74 undergoing orthotopic heart transplantation, outcomes are comparable to those in younger individuals [101]. However, due to low availability of donor hearts, few individuals are selected for transplantation and they generally have low rates of co-existing diseases. To address this disparity, some centers are performing the procedure using hearts from older donors for an increasing number of older adults who previously would have been declined for transplantation.

Left ventricular assist devices (LVADs) for destination therapy (DT) are increasingly used in patients with advanced heart failure with reduced left ventricular ejection fraction who are ineligible for heart transplantation [102, 103]. As a result, many DT-LVAD candidates are older and have greater comorbidity than younger device candidates. LVAD implantation is associated with substantial morbidity and mortality despite improvements in device technology and operative skills. Currently, 2-year survival rates following LVAD implantation are less than 60 %, the overall stroke rates is 11 % [102], and 5-year costs are >$350,000 [104]. For these reasons optimal patient selection for DT-LVAD implantation is critical.

The prevalence of frailty in patients with advanced heart failure approaches 50 % as a result of reduced cardiac output, deconditioning, cognitive impairment, and muscle cachexia [105]. Additionally, hallmark symptoms of advanced heart failure, including exhaustion, reduction in physical activity, and weakness are also fundamental components of frailty. The presence of frailty and/or cognitive impairment negatively impacts short- and long-term outcomes. Whether elements of frailty can be reversed with restoration of adequate cardiac output has not been determined. The concept of “LVAD responsive” and “LVAD un-responsive” frailty has been proposed in an effort to optimize patient selection for DT-LVAD implantation, but additional studies are needed. Heart Failure with Preserved Ejection Fraction

Up to 50 % of patients with heart failure have normal or near normal LV ejection fractions [i.e., heart failure with preserved ejection fraction (HFpEF) ]. The majority of patients with HFpEF have antecedent hypertension (60–80 %), and HFpEF prevalence is substantially higher in women than in men. Multimorbidity is common and often includes other CV disorders, such as CAD, atrial fibrillation , and valvular heart disease. Although prognosis is somewhat better for HFpEF than for HFrEF, symptoms, quality of life, and hospitalization rates are similar between the two forms of heart failure. However, unlike HFrEF, for which numerous therapies have been shown to improve symptoms and clinical outcomes, to date no pharmacological or device-based interventions have demonstrated efficacy in HFpEF (Table 21.5). For this reason, current management of HFpEF focuses on optimizing blood pressure control (see above Sect. 23.3.1), treating ischemia in patients with concomitant CAD, controlling heart rate in patients with atrial fibrillation, and avoiding excess dietary salt and fluid intake. Diuretics are indicated to maintain euvolemia and minimize symptoms of shortness of breath and edema, but must be used judiciously to avoid over-diuresis, which may lead to reduced organ perfusion and pre-renal azotemia.

Table 21.5
Clinical trials in heart failure with preserved ejection fraction


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Aug 25, 2017 | Posted by in GERIATRICS | Comments Off on Cardiovascular Disease

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