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7 - Cardiovascular Disorders |
177
to use these medications as a result of comorbid
disease states such as osteoarthritis. Acetamino-
phen should be recommended in lieu of NSAIDs
.
A few recent studies have demonstrated a
possible link between heart failure and cognitive
impairment or dementia. Proposed mechanisms
include decreased cerebral blood flow, leading
to further ischemia and possibly degeneration of
neurons.
70-72
Further analyses are needed, but it
is reasonable to perform cognitive screening in
elderly patients with heart failure.
A F
Etiology, Epidemiology, and
Clinical Presentation in Geriatric
Population
The prevalence of atrial fibrillation increases with
aging. Atrial fibrillation is present in approximately
0.5% of patients between 50 and 59; in individ-
uals >65, the prevalence is roughly 5% and rises
to 8% and 10% in patients >80 years.
73,74
The
incidence of atrial fibrillation is <0.1% per year in
individuals under 40 but increases to 1.5% and
2.0% per year in women and men, respectively,
over 80.
75
Atrial fibrillation is associated with a two-
fold increase in the incidence of cardiovascular
mortality. It increases the risk for ischemic stroke
fivefold and is responsible for approximately 15%
of all strokes in the United States.
76
Atrial fibrilla-
tion may be responsible for as many as 24% of all
strokes in individuals between 80 and 89.
77
Risk factors for atrial fibrillation include
hypertension, coronary artery disease, heart
failure, valvular heart disease, and rheumatic
heart disease. The common feature of these
conditions is the development of left atrial hyper-
trophy, which leads to derangements in atrial
impulse conduction and refractoriness. Hyper-
thyroidism is a potentially correctable cause
of atrial fibrillation. This arrhythmia may occur
following thoracic surgery, including coronary
artery bypass graft surgery, pulmonary resec-
tion, or esophagectomy. In these situations,
the arrhythmia is usually transient, lasting only
a few days. Drug-induced atrial fibrillation is
uncommon but has been reported in associa-
tion with binge drinking of alcohol (the so-called
“holiday heart” syndrome). In addition, bisphos-
phonate drugs have recently been associated
with inducing new cases of serious atrial fibril-
lation; this is particularly pertinent to the elderly
population, as many elderly patients with osteo-
porosis take these drugs for prevention of frac-
tures. The association between bisphosphonate
drugs and new-onset serious atrial fibrillation is
not certain and requires further study.
Atrial fibrillation appears on the ECG as
an irregularly irregular rhythm with no visible p
waves, but rather an undulating baseline, repre-
senting chaotic atrial electrical activity. Ventric-
ular rates during atrial fibrillation generally range
from 100 to 180 beats per minute. Symptoms
associated with atrial fibrillation are typically
dependent on the ventricular rate and include
palpitations, dizziness, lightheadedness, near-
syncope, syncope, shortness of breath, and, in
patients with underlying coronary artery disease,
angina. Elderly patients have atypical presenta-
tions or may be asymptomatic. An evaluation of
pulse may reveal irregular heart rate in an other-
wise asymptomatic individual. In some patients,
the first symptom of atrial fibrillation is a stroke.
Depending on the degree to which cardiac
output is compromised, patients may become
hypotensive and hemodynamically unstable.
Standard Adult Treatment
Recommendations
Treatment recommendations are provided in the
2013 ACC/AHA Task Force on Practice Guide-
lines Report: Management of Patient with Atrial
Fibrillation and the 2012 American College
of Chest Physicians Evidence-Based Clinical
Practice Guidelines: Antithrombotic Therapy
for Atrial Fibrillation.
75,78
The primary goals of
therapy include ventricular rate control, conver-
sion to sinus rhythm, reduction in the frequency
of episodes (for patients with paroxysmal atrial
fibrillation), and stroke prevention.
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| Fundamentals of Geriatric Pharmacotherapy
Ventricular Rate Control
Diltiazem, verapamil, and a beta
blocker are
first-line agents for controlling ventricular rate. If
those medications are contraindicated for rate
control, digoxin or amiodarone is recommended.
The 2012 Beers Criteria supports this by stating
antiarrhythmics should not be used first-line for
atrial fibrillation. The goal of therapy is reduction
in ventricular rate to <100 BPM or, if that cannot
be achieved, reduction in ventricular rate >20%
from the pretreatment value with alleviation of
patient symptoms.
75
Conversion to Sinus Rhythm
Conversion of atrial fibrillation to sinus rhythm
is safe in patients in whom the episode of atrial
fibrillation has persisted for <48 hours. However,
if the patient’s episode of atrial fibrillation has
persisted ≥48 hours or if the duration is unknown,
conversion to sinus rhythm with direct current
cardioversion (DCC) or drugs may be dangerous
because after 48 hours the possibility exists
that a clot may have formed in the left atrium.
The process of converting atrial fibrillation to
sinus rhythm may dislodge the clot and cause
a stroke. Therefore, in many institutions a trans-
esophageal echocardiogram (TEE) is performed
in patients with atrial fibrillation ≥48 hours or of
unknown duration. If a left atrial clot is detected
by TEE, conversion to sinus rhythm is deferred,
and anticoagulation is initiated for at least 4
weeks. However, if no left atrial clot is detected
by TEE, sinus rhythm may be restored.
75
Although there are no comparative trials
of DCC versus drug therapy, DCC is generally
believed to be more effective. Pharmacological
conversion of atrial fibrillation to sinus rhythm
may be achieved with dofetilide, ibutilide, amio-
darone, propafenone, or flecainide, and the
exact agent is selected according to presence
of contraindications
.
Reduction in the Frequency of Episodes
of Atrial Fibrillation
This goal of therapy is commonly expressed as
maintenance of sinus rhythm. Several random-
ized studies have compared rate-control and
rhythm-control strategies and found no advan-
tage to rhythm-control therapy with respect to
mortality or stroke. However, some data gener-
ated in these studies suggested that there may
be trends toward worse outcomes, including
mortality, associated with rhythm control strate-
gies, presumably as a result of proarrhythmic
effects of the drugs. Therefore, drug therapy for
reduction of frequency of episodes should be
reserved for patients with paroxysmal atrial fibril-
lation who continue to experience symptoms
despite optimal doses of drugs for ventricular
rate control.
75
Propafenone, flecainide, amiodarone,
sotalol, or dofetilide are potential choices for
maintenance of sinus rhythm; however, propafe-
none and flecainide are contraindicated in
patients with left ventricular dysfunction. Amio-
darone has been shown to be more effec-
tive than sotalol, is rarely associated with the
proarrhythmia known as torsades de pointes,
and, therefore, is a preferred drug by many clini-
cians; however, amiodarone is associated with
a long list of noncardiovascular adverse effects,
including pulmonary fibrosis, thyroid dysfunction,
hepatotoxicity, photosensitivity, blue-grey skin
discoloration, corneal microdeposits, and others.
Stroke Prevention
The CHADS
2
score is a tool that helps to esti-
mate stroke risk in patients with atrial fibrillation.
The CHADS
2
scoring is shown in Table 7-3. The
CHA
2
DS
2
-VASC scoring tool also may be consid-
ered when establishing stroke risk. This tool was
not included in some of the current guidelines
and no guidelines currently recommend it over
the CHADS
2
score; however, CHA
2
DS
2
-VASC
does take into account gender, presence of
vascular disease, and risk in the 65–74-year age
group. CHA
2
DS
2
-VASC may be considered in
those with a low CHADS
2
score of 0–1 to help
further assess risk. A summary of ACCP recom-
mendations for stroke prevention in the general
adult population can be found in Table 7-2.
75,78
These recommendations are typically based
on the CHADS
2
score of an individual patient.
Aspirin, warfarin, dabigatran, rivaroxaban, and
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179
apixaban may all be alternatives given the
patient’s risk and individual patient factors, as
shown in Table 7-2, for nonvalvular atrial fibril-
lation. For patients with valve disease or pros-
thetic heart valves, warfarin is the anticoagulant
of choice for stroke prevention.
78
Treatment Recommendations in
Geriatric Population
Treatment recommendations for ventricular
rate control, conversion of atrial fibrillation to
sinus rhythm, and reduction of the frequency
of episodes for patients with paroxysmal atrial
fibrillation are the same in elderly as in younger
patients. Age does play a factor in stroke preven-
tion.
78,79
Based on the ACCP guidelines, patients
at intermediate risk for stroke (i.e., a CHADS
2
score of 1) should be on oral anticoagulation.
78
Age 75 years and over alone would create a
CHADS
2
score of 1. For patients in this group
who choose not to take oral anticoagulation,
recommend clopidogrel 75 mg with aspirin.
78
Dabigatran, rivaroxaban, and apixaban are
also approved for stroke prevention in nonval-
Table 7-2. Statin Therapy Intensity
27
High Intensity Moderate Intensity Low Intensity
Atorvastatin 40–80 mg daily
Rosuvastatin 20–40 mg daily
Atorvastatin 10–20 mg daily
Rosuvastatin 5–10 mg daily
Simvastatin 20–40 mg daily
Pravastatin 40–80 mg daily
Lovastatin 40 mg daily
Fluvastatin 40 mg twice daily or
80 mg daily XL
Pita
vastatin 2–4 mg daily
Simvastatin 10 mg daily
Pravastatin 10–20 mg daily
Lovastatin 20 mg daily
Fluvastatin 20–40 mg daily
Pitavastatin 1 mg daily
Table 7-3. Stroke Prevention in Atrial Fibrillation–CHADS
2
Risk Stratification
78
CHADS
2
Score
Degree of
Stroke Risk Recommended Stroke Prevention Strategy
0 Low No therapy
1 Intermediate Nonvalvular: oral anticoagulation with
•
warfarin (INR 2–3)
• dabigatran
•
rivaroxaban
• apixaban
Valvular: warfarin (INR 2–3 or 2.5–3.5)
≥2 High Nonvalvular: oral anticoagulation with
•
warfarin (INR 2–3)
•
dabigatran
• rivaroxaban
• apixaban
Valvular: warfarin (INR 2–3 or 2.5–3.5)
CHADS
2
score calculated as follows:
C
ongestive heart failure 1 point
H
ypertension 1 point
A
ge ≥75 years 1 point
D
iabetes mellitus 1 point
S
troke or TIA history 2 points
INR, international normalized ratio; TIA, transient ischemic attack.
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| Fundamentals of Geriatric Pharmacotherapy
vular atrial fibrillation; they are acceptable
alternatives to warfarin. However, these newer
agents have not been studied as extensively
in the elderly. The efficacy and some of the
safety issues with these newer anticoagulants is
discussed further in this section.
The Randomized Evaluation of Long-Term
Anticoagulation Therapy (RE-LY) trial looked at
dabigatran use in nonvalvular atrial fibrillation in
over 18,000 patients. The average age in this trial
was 71, and the follow-up was approximately 2
years. The interventions were warfarin versus
dabigatran 110 mg twice daily or dabigatran
150 mg twice daily. The trial showed noninferiority
of dabigatran 150 mg twice daily with warfarin
and was given FDA approval for this indication. The
primary outcome was stroke or systemic embolism.
The reduction was consistent across all CHADS
2
categories.
80
In subgroup analyses of bleeding,
age over 75 years and CrCl <30 mL/min were risk
factors: an increase of as much as 20%.
80
These
data led to the inclusion of dabigatran on the
Beers Criteria.
81
The Rivaroxaban Versus Warfarin in
Nonvalvular Atrial Fibrillation (ROCKET AF) trial
compared rivaroxaban to warfarin in more than
14,000 patients. The primary outcome was again
stroke or systemic embolism, and follow-up was
2 years. The average age of patients in this trial
was 73. This trial showed noninferiority of rivarox-
aban to warfarin. The safety outcomes included
major bleeding such as intracranial hemorrhage.
There was no significant difference between the
two groups.
82
The Apixaban Versus Warfarin
Patient with Atrial Fibrillation (ARISTOTLE) trial
enrolled more than 18,000 patients and had a
mean follow-up of 1.8 years. The average age of
patients in this trial was 70. The primary outcome
was also stroke or systemic embolism. Apixaban
was shown to be noninferior to warfarin. There
was a trend toward less bleeding with apixaban.
83
All three of these new agents are FDA
approved for use in the geriatric population, and
the ages and CHADS
2
scores in the major trials
of these agents included various subgroups
of geriatrics. Efficacy was established in some
subgroups; however, there are several barriers
that may limit use of these agents in specific
patients. One of the major drawbacks of each
of these new anticoagulants versus warfarin is
the lack of an antidote to bleeding. Clearance of
these agents may be longer in geriatrics, leading
to longer recovery when a patient is bleeding,
or if an emergent surgery is needed. Further
discussion of the specific subgroups in which
these newer anticoagulants may be problematic
is discussed in the next section.
Barriers to Treatment in the
Geriatric Population
Elderly patients are at greater risk for adverse
effects associated with some of the anti-
arrhythmic agents used for the management of
atrial fibrillation. For example, elderly patients
are more likely to experience constipation asso-
ciated with verapamil or diltiazem. In addition,
drugs such as sotalol, ibutilide, and dofetilide
are associated with the risk of the potentially life-
threatening ventricular arrhythmia known as tors-
ades de pointes; elderly patients are at greater
risk of experiencing this drug-induced pro-
arrhythmia. Furthermore, as a result of declining
kidney function elderly patients may be at higher
risk of experiencing elevated serum digoxin
concentrations and associated digoxin toxicity.
A number of the adverse effects associated with
amiodarone occur with increased frequency in
elderly patients, including sinus bradycardia,
hypothyroidism, pulmonary fibrosis, and neuro-
logic adverse effects such as ataxia, tremor,
peripheral neuropathy, insomnia, and impaired
memory. As a result of these considerations,
digoxin (at doses >0.125 mg daily) and amioda-
rone, dofetilide, dronedarone, flecainide, ibuti-
lide, procainamide, propafenone, quinidine, and
sotalol first-line for atrial fibrillation are included
in the Beers Criteria for potentially inappropriate
drug use in older adults.
81
There are numerous considerations for the
use of warfarin and some of the newer antico-
agulants in elderly patients, which are discussed
here and in the Venous Thromboembolism
section of this chapter.
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181
Warfarin
Conflicting data exist regarding whether elderly
patients are at increased risk of bleeding
complications associated with warfarin therapy.
However, it is well established that the risk of
warfarin-induced bleeding is increased in the
very old population (patients >80). Warfarin
therapy is not contraindicated in this population,
but careful monitoring of international normalized
ratio (INR) and signs and symptoms of bleeding
is warranted. In addition, many elderly patients
are at risk of falls; in patients with a history of
falls, or who appear to be at risk of falling, careful
assessment of the risks and benefits of warfarin
therapy is often performed. Conventional thinking
has been that if a therapeutically anticoagulated
patient falls and hits his or her head, an intra-
cranial hemorrhage may result, which may be as
catastrophic as a thromboembolic stroke. In the
frail elderly population who are at risk of falling,
aspirin is often substituted for warfarin because
of the risk of intracranial hemorrhage.
However, evidence suggests that the risk of
a patient falling and experiencing a significant
cerebral bleed during warfarin therapy is low.
Man-Son-Hing et al.
84
utilized a Markov deci-
sion model incorporating previously published
literature regarding the risk of accidental fall
and cerebral bleeding during warfarin therapy
in patients 65 or older. The authors concluded
that warfarin therapy was associated with a
larger number of quality-adjusted life-years than
aspirin therapy or no antithrombotic therapy
(12.90 versus 11.17 versus 10.15, respectively).
In addition, the authors concluded that, based
on sensitivity analysis, the risk of falling was not
an important determining factor of optimal anti-
thrombotic therapy. Therefore, perceived risk of
falling may not be a sufficiently important factor
to discourage warfarin administration for stroke
prevention in elderly patients with atrial fibrillation.
Because elderly patients are usually taking
a substantially larger number of medications
than younger patients, there is a greater poten-
tial for drug interactions associated with warfarin
that could increase the risk of supratherapeutic
INR and bleeding. Careful assessment of
concomitant drug therapy, particularly drugs that
inhibit the function of CYP450 2C9, and appro-
priate adjustment of warfarin dose, if needed, is
important in the elderly population. This is often
especially problematic with antibiotic drugs, as
these are usually prescribed on an acute, short-
term basis. Routine warfarin monitoring sched-
ules cannot always capture INR excursions
caused by interaction as antibiotic prescribing
will not often coincide with a predictable
schedule, so the ability to identify a drug interac-
tion is dependent on prospective drug regimen
review by the prescriber and pharmacist at the
time of antibiotic initiation.
There are several tools that attempt to esti-
mate bleeding risk in patients. The Outpatient
Bleeding Risk Index (OBRI) takes into account
four risk factors: (1) age ≥65 years, (2) history
of stroke, (3) history of GI bleeding, and (4)
one or more of the following: recent MI, hema-
tocrit <30%, serum creatinine >1.5 mg/dL, and
diabetes mellitus. Each of these four categories
counts as 1 point. Those scoring 0 are at low
risk, 1–2 are at intermediate risk, and ≥3 at high
risk. The corresponding risks of major bleeding
at 48 months were 3%, 12%, and 53%.
85
The
HAS-BLED score has been used to determine
bleeding risk in atrial fibrillation patients. There
are 9 points that can be given: hypertension,
abnormal liver function, abnormal kidney func-
tion, stroke, bleeding tendency, labile INRs,
elderly (age >65), alcohol abuse, and drugs
(taking aspirin or NSAIDs). If a patient scores 0
points that corresponds to 1.13 bleeds per 100
patient years; 1 point is 1.02 bleeds, 2 points is
1.88 bleeds, 3 points is 3.74 bleeds, and 4 points
is 8.70 bleeds. There are no data to support esti-
mation of bleeds for scores of 5–9.
86
Both of these
tools can be used to help determine whether the
risk of bleeding in elderly patients outweighs the
risk of stroke of thromboembolism.
Dabigatran
As discussed above, the bleeding risk with
dabigatran is likely higher in those 75 years and
older and those with CrCl <30 mL/min. Also,
there are administration issues to consider when
using dabigatran in the geriatric population. The
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| Fundamentals of Geriatric Pharmacotherapy
capsules cannot be opened and sprinkled on
food, restricting use of this medication to those
who do not have swallowing issues. They must
be kept in their original bottle and cannot be
placed in a medication organizer. The elderly
tend to have complex regimens in which an
organizer is needed; adherence to dabigatran
therapy might be affected if the medicine must
be omitted from organizers. In addition, dabiga-
tran is metabolized by p-glycoprotein; therefore,
interaction with p-glycoprotein must be taken in
to account. Agents specifically listed for dose
adjustment include dronedarone and oral keto-
conazole.
87
Rivaroxaban
Rivaroxaban is metabolized by CPY3A4, and
drug interactions need to be taken in to account
when deciding whether this agent should be used.
There are also dose limitations with renal function.
If CrCl is 15–50 mL/min, a reduced dose of rivar-
oxaban should be used. If CrCl is <15 mL/min, the
medication should not be used. There is slightly
different renal dosing for the indication of venous
thromboembolism discussed in that section.
88
Apixaban
This medication is metabolized by CYP3A4
as well. Drug interactions must be taken in to
account when deciding whether to initiate this
agent. There are recommendations regarding
when to reduce the dose of apixaban that are not
based completely on renal function. Systemic
exposure seems to be increased with age, sepa-
rate from renal function. If a patient has a serum
creatinine of 1.5 mg/dL or higher and has one
of the following: age ≥80 years or body weight
≤60 kg, a reduced dose of apixaban should
be used. It is also recommended if CrCl is
<25 mL/min, apixaban should be avoided.
89
Cost is also a consideration with the new
anticoagulants. The price of these medications
is significantly higher than warfarin; however,
there is less cost for monitoring. The copays may
be higher and prior authorizations required for
use of these agents for those on Medicare Part
D plans. Patients should also be prepared to
encounter the “doughnut hole” gap in coverage
with many Medicare Part D plans faster due to
the cost of these medications.
KEY POINT:
e newer anticoagulants
may be used in some geriatric patients
after careful evaluation of the drugs’ safety
in each individual patient. Extra attention
should be paid to renal function, signicant
drug interactions, medication adherence
history, need for immediate procedures,
insurance coverage, and bleeding risk when
considering initiating these new agents.
S
Etiology, Epidemiology, and
Clinical Presentation in the
Geriatric Population
Stroke is a significant cause of morbidity, and
is the third leading cause of death in the United
States. The risk of stroke doubles every 10 years
after the age of 55.
21,90
The cost of stroke care is
high because many patients have residual effects,
and it was estimated to be $68.9 billion in 2009.
21
The incidence of mortality associated with
stroke rises with age, demonstrating a need for
prevention and education in the geriatric popula-
tion. Median survival after a first stroke in patients
age 60–69 is 6.8 years for men and 7.4 years for
women. In patients 80 and older, median survival
is 1.8 years for men and 3.1 years for women.
21
As many as 26% of patients receive institutional-
ized care after stroke.
21
Risk factors for stroke,
such as hypertension and atrial fibrillation, also
are more prevalent in geriatrics.
Ischemic stroke accounts for approximately
87% of cases, whereas hemorrhagic stroke
accounts for the remaining 13%.
21
This ratio takes
into account all age groups and is representa-
tive of the older population. Clinical presentation
does not differ greatly in the geriatric population.
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Co-morbid disease states, such as dementia,
may make recognition of stroke symptoms
more difficult. Patients and caregivers require
significant education about recognizing stroke,
because the timing of treatment following onset
is an important factor in determining outcome.
Standard Adult Treatment
Recommendations
The standard of care for stroke is discussed in
the AHA/ASA guidelines and the 2012 ACCP
guidelines on stroke.
90,91
The source (hemorrhagic, noncardio-
embolic, cardioembolic) and time of onset of
symptoms are important factors in treatment.
Thrombolytic therapy should only be used if the
presentation is within 3 hours of onset and the
etiology of the stroke is ischemic. The only FDA-
approved thrombolytic drug for management
of ischemic stroke in the United States is tissue
plasminogen activator (t-PA), and patients must
be evaluated for inclusion and exclusion criteria
for its use. The source of the stroke affects
whether antiplatelet or anticoagulant treat-
ment is administered for secondary prevention.
Cardioembolic strokes should be prevented with
warfarin. Noncardioembolic strokes should be
prevented with aspirin, clopidogrel, or aspirin–
extended-release dipyridamole.
The optimal antiplatelet medication for
secondary prevention of stroke is not completely
clear. Aspirin, extended-release dipyridamole
with aspirin, and clopidogrel all are acceptable
choices per guidelines. The AHA/ASA guide-
lines have suggested that extended-release
dipyridamole with aspirin may be a better choice
based on the European/Australian Stroke Preven-
tion in Reversible Ischaemia Trial (ESPRIT) and
other previous trials.
92
Since publication of the
AHA/ASA guidelines, the Prevention Regimen
For Effectively Avoiding Second Strokes
(PRoFESS) trial has been published, in which the
efficacy of clopidogrel was compared with that of
extended-release dipyridamole combined with
aspirin for secondary prevention of strokes.
93
In
this study, the efficacy of both treatment strate-
gies on stroke recurrence was similar. All these
therapies remain first-line options, although cost
is a significant factor, as aspirin therapy costs
much less than the other two therapeutic strat-
egies. Future studies are required to determine
whether there is a clear benefit with any of the
specific treatments.
Ticlopidine is an alternative agent for
patients who cannot tolerate other antiplatelets.
Use of ticlopidine is quite limited due to adverse
effects, including bone marrow suppression,
diarrhea, and aplastic anemia. Transient isch-
emic attack should be considered reason for
secondary prevention.
The Management of Atherosclerosis with
Clopidogrel in High-Risk Patients (MATCH) trial
evaluated the efficacy of the addition of aspirin
therapy to clopidogrel for reducing the incidence
of vascular events, including stroke.
94
This trial
included patients with a history of stroke within
the previous 3 months plus additional risk factors
for vascular events. All patients received clopido-
grel 75 mg daily and were randomized to receive
either aspirin 75 mg daily or placebo. The study
found no significant decrease in vascular events
with the combination of aspirin and clopidogrel
compared with clopidogrel alone. However,
there was a significantly higher incidence of
life-threatening bleeding in patients treated with
the combination of clopidogrel and aspirin.
94
Therefore, combination therapy with clopidogrel
and aspirin is not recommended for secondary
prevention of stroke.
Treatment Recommendations in the
Geriatric Population
The majority of the trials used in development
of the national guidelines for stroke included
patients over age 65, most with a mean age in
the 60s. The guidelines are applicable to most
geriatric patients, with special considerations
discussed in this section. However, the subgroup
of patients over 80 was not as well represented
in this evidence base.
The National Institute of Neurological
Disorders and Stroke (NINDS) study of the effi-
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184
| Fundamentals of Geriatric Pharmacotherapy
cacy of tissue plasminogen activator for isch-
emic stroke enrolled patients with mean age of
67 ± 10 years.
95
There have been several follow-
up studies specifically in patients over 80. In
general, these studies have shown that thrombo-
lytic therapy should not be withheld in patients
with stroke who are ≥80 years, if other criteria for
receiving the medication are met. Although some
trials showed that a higher proportion of younger
patients achieved a favorable outcome associ-
ated with thrombolytic therapy than in patients
≥80 years, there was still benefit reported in the
very elderly.
96-98
The lower proportion of patients
≥80 years who benefitted from thrombolytic
agents may be partially explained by the larger
number of comorbid conditions in the very old,
and the fact that they experienced more severe
strokes in some trials. Several of the studies
were retrospective reviews or post hoc analyses
of data and must be interpreted in that context.
However, there is much evidence that age should
not be an automatic exclusion to thrombolytic
therapy.
96-99
The Chinese Acute Stroke Trial
(CAST)
100
and the International Stroke Trial (IST)
101
were major studies that established the benefit
of early aspirin therapy in patients with ischemic
stroke, and their data are applicable to the geri-
atric population who cannot receive thrombolytic
therapy. In the CAST trial, 28% of patients were
over 70, whereas 26% of patients enrolled in the
IST trial were ≥80 years of age.
100,101
Several of the landmark trials of secondary
prevention of stroke included patients over 65,
and secondary prevention recommendations
should be applied to all age groups. The Anti-
thrombotic Trialists’ Collaboration investigated
the efficacy of antiplatelet therapy in patients
over age 65 and reported that this group derives
benefits similar to younger patients.
91
Some
studies have shown lower rates of appropriate
anticoagulation or antiplatelet therapy after
stroke in the geriatric population, and it should
be emphasized that the use of these agents for
secondary prevention should be advocated in
elderly patients, as this is often the highest risk
group. The role of primary prevention in the geri-
atric population, especially the very old, is not as
clear, as there are few data. If a patient’s 10-year
risk for coronary heart disease is >10%, primary
prevention should be considered. Future trials
should provide more guidance.
Hormone replacement therapy for older
women has been found to increase the risk of
stroke and should be avoided or used for the
shortest duration possible. Post-stroke depres-
sion, dementia, and the development of seizures
are common, as is dysphagia (discussed in
Chapter 10), functional decline associated with
loss of mobility or contractures, and somnolence.
Antidepressants, cholinesterase inhibitors,
memantine, antiepileptics, nutritional supple-
ments, appetite stimulants, muscle relaxants,
and psychomotor stimulants are often added
to a patient’s regimen as interventions for these
problems. In such instances, critical evaluation
of patient outcomes is necessary, as this is often
a source of polypharmacy-related problems.
Barriers to Treatment in the
Geriatric Population
A potential barrier to early presentation of stroke
in geriatrics is transportation to the emergency
department. It should be stressed that patients
must call 911 immediately if stroke symptoms
occur.
KEY POINT:
Patients and caregivers
should be educated to recognize the
symptoms of stroke, allowing them to get
to the emergency department sooner.
There is a risk of bleeding in association
with any of the above medications used for
acute treatment or prevention. Some evidence
shows small increases in bleeding risk associ-
ated with these agents as age increases, but
there is also evidence to the contrary. The risks
and benefits of therapy in each patient must be
weighed. Factors such as frailty, falls, previous GI
bleed, peptic ulcer disease, polypharmacy, life
expectancy, and patient preference should be
weighed. Specific concerns with warfarin in the
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7 - Cardiovascular Disorders |
185
geriatric population are discussed in the Venous
Thromboembolism section and are pertinent to
stroke. The lowest possible drug doses should
be used in the elderly, including aspirin 81 mg.
Dose adjustment for geriatric patients
with kidney and/or hepatic disease is always a
consideration, as there is age-related decline in
kidney and hepatic function. Extended-release
dipyridamole with aspirin and aspirin mono-
therapy should be avoided in patients with esti-
mated CrCl <10 mL/min, and clopidogrel therapy
should be avoided in patients with severe kidney
disease. Dipyridamole should also be used with
caution in patients with severe hepatic impair-
ment. Caution should also be exercised in older
patients with syncope or orthostatic hypoten-
sion, as dipyridamole can exacerbate these
conditions due to its vasodilatory properties.
V T
Etiology, Epidemiology, and
Clinical Presentation in the
Geriatric Population
The incidence of venous thromboembo-
lism (VTE) is higher in the geriatric popula-
tion compared with that in younger patients.
Age should be considered when assessing a
patient’s risk of VTE. In a large study of 342,000
patients in France, the overall rate of VTE in the
population was 1.83/1000 patients but 10/1000
in patients 75 or older.
102
In addition to this higher
risk, mortality associated with VTE is also higher
in the geriatric population.
Risk factors for VTE, including malignancy,
hormone replacement therapy, heart failure,
severe lung disease, major surgery, and use
of erythropoiesis-stimulating agents are more
common in geriatrics. Immobility also plays a
large role in determining risk. Paralysis from
stroke can cause significant immobility, and
recovery after surgery or procedures may put
geriatric patients at higher risk. Older adults tend
to have several of these risk factors, which are
cumulative in conferring risk.
Orthopedic procedures such as total hip
replacement, total knee replacement, and hip
fracture surgeries are common in geriatrics.
Immobility after these procedures carries a
higher risk. Incidences of deep-vein thrombosis
(DVT) from 7 to 14 days after these procedures
in patients not undergoing VTE prophylaxis are
as high as 40% to 60%.
103-105
The administration
of VTE prophylaxis reduces these incidences to
1% to 10% in the 3 months following surgery.
103-
105
Geriatric patients need aggressive monitoring
and appropriate prophylaxis to prevent higher
morbidity and mortality after these procedures
and during their rehabilitation.
The clinical presentation of VTE in geriatrics
is similar to that in younger people. Diseases such
as heart failure and chronic obstructive pulmo-
nary disease that occur more frequently in the
older population can complicate the diagnosis of
pulmonary embolism. Changes in the frequency
or quality of shortness of breath and chest pain
can be more difficult to detect in patients with
those diseases, and symptoms related to those
diseases can fluctuate. In addition, heart failure
can cause significant lower extremity edema,
which can complicate the diagnosis of DVT,
although edema associated with DVT is typically
unilateral. Advanced diabetic neuropathy and
paralysis from stroke can also cause difficulty in
recognizing changes in pain and temperature in
lower extremities.
Standard Adult Treatment
Recommendations
New guidelines for prevention and treatment
of VTE were released in 2012 by ACCP.
103-106
Risk assessment should be performed for each
hospitalized patient and written policies and
protocols should be in place to specify appro-
priate prophylaxis measures. Both mechanical
and pharmacological methods are described
in the guidelines. Treatment of acute VTE
should be performed in an outpatient setting if
possible, using low molecular weight heparin
(LMWH) or fondaparinux initially.
106
Duration of
treatment depends on risk factors and identifi-
cation of the cause of VTE. No distinctions are
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186
| Fundamentals of Geriatric Pharmacotherapy
made regarding the geriatric population in the
guidelines, with the exception of recommending
extra attention to dose adjustments of antico-
agulants in those with kidney disease. Warfarin
is the recommended long-term anticoagulant in
the current guidelines. Rivaroxaban is an alter-
native to warfarin and has shown noninferiority
to warfarin in treatment of VTE. Specific recom-
mendations regarding VTE prevention in patients
undergoing total hip and knee replacement or hip
fracture surgeries are in the guidelines, as these
procedures are commonly performed in geriat-
rics.
105
Bleeding, kidney function, and develop-
ment of postthrombotic syndromes should be
monitored. Graduated compression stockings
are recommended for prevention of postthrom-
botic syndrome for proximal DVT.
Treatment Recommendations in the
Geriatric Population
The ACCP guidelines provide a strong basis for
treatment recommendations; the majority of the
analyses that form the basis for the guidelines
include many patients over age 65, and some
above 80 years.
103-106
Treatment recommen-
dations for prevention of VTE should be advo-
cated for geriatrics. There is some evidence that
physicians are less likely to use anticoagulation
therapy in older people. The risk versus benefit
ratio for VTE management is clearer than with
indications such as atrial fibrillation, for which
there may be more treatment alternatives.
However, with respect to prophylaxis of VTE,
physicians’ attitudes regarding risks associated
with anticoagulation in elderly patients may be
more of a factor. Mechanical methods should
not be the sole method of prophylaxis, unless
the patient is at high risk for bleeding. LMWH,
fondaparinux, or warfarin should be used for VTE
prophylaxis in patients undergoing total knee
and total hip replacement. For patients under-
going hip fracture surgery, an additional option
is low-dose unfractionated heparin.
105
Consider-
ations for dose adjustment of these agents for
kidney disease are discussed below.
The duration of prophylaxis should be at
least 10 days and up to 35 days after orthopedic
surgery. Immobility and speed of recovery must
be considered, and the duration of prophylaxis
may need to be extended, depending on the
course of recovery. Evidence for routine prophy-
laxis in nursing home patients and homebound
geriatrics is not established, and no recommen-
dations can be made.
107
Evidence for treatment of VTE in geriatric
patients is very similar to that in younger adults.
The majority of the studies that form the basis
for the ACCP guidelines include older adults.
LMWH and fondaparinux administration facili-
tates outpatient treatment of DVT, which should
be a goal for older patients as well. It is recom-
mended that unfractionated heparin be used for
initial treatment in patients with severe kidney
disease, which could encompass some of the
geriatric population. The duration of anticoagu-
lation treatment of VTE depends, in part, on the
number of VTE events experienced and whether
risk factors can be eliminated. If immobility was
a suspected cause of VTE, and is not expected
to change, an older patient may continue anti-
coagulation treatment for longer than the recom-
mended 3 months, even after a first event. Inten-
sity of anticoagulation with warfarin for long-term
treatment of VTE in the geriatric population
should be an INR of 2.0–3.0.
The use of thrombolytic agents for manage-
ment of pulmonary embolism should be reserved
for patients with hemodynamic compromise.
108
Contraindications for use of thrombolytics for
pulmonary embolism include history of cere-
brovascular accident, which may prohibit their
use in geriatrics.
108
Precaution should be used
in patients older than 75 years, due to increased
bleeding risk.
108
Several issues pertaining to elderly patients
must be considered regarding therapy with
warfarin, which is used for long-term treatment
of VTE and also for VTE prophylaxis. The initial
recommended warfarin dose in elderly patients
is ≤5 mg daily, according to the ACCP guide-
lines.
109
In a large cohort study that included
2,359 patients ≥80 years of age, average
weekly doses of warfarin were analyzed, strati-
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