Download Valvular Heart Disease: A Primer for the Clinical Pharmacist

Valvular Heart Disease:
A Primer for the Clinical Pharmacist
Tammy J. Bungard, Pharm.D., and Brian Sonnenberg, M.D.
Valvular heart disease is a commonly encountered clinical condition that is
not taught in most undergraduate and graduate pharmacy programs, leaving
the practicing pharmacist without basic knowledge to expand on and
subsequently apply to direct patient care. Unlike other areas of cardiology in
which thousands of patients are recruited in many well-designed randomized
clinical trials, data assessing treatments for valvular heart disease are limited
and often consist of retrospective case series or observations. Our goal is to
provide a basic overview of chronic valvular heart disease, with emphasis on
describing the common conditions requiring surgery and the available
options, as well as common pharmacologic therapies used in this patient
population. Anomalies in valves can be broadly classified as stenosis and
regurgitation. Depending on the valve and the type of anomaly, the impact on
the cardiovascular system will vary. Understanding the hemodynamic
consequences of aortic stenosis, aortic regurgitation, mitral stenosis, and
mitral regurgitation is imperative to effectively counsel patients surrounding
disease progression and self-monitoring, use of vasodilators, and prophylaxis
for endocarditis and rheumatic fever. Further, patient characteristics factored
into the choice of implanting either a bioprosthetic (tissue) or prosthetic
(metal) valve encompass patient choice, life expectancy, and willingness or
ability to accept lifelong anticoagulation therapy. The evolution of metal
valves has resulted in newer generations under clinical study that have more
laminar flow (minimizing interaction with blood products) and improved
pyrolytic carbon (minimizing infection and interaction with blood products).
Although antithrombotic therapy with warfarin is now mandatory in North
America for all patients receiving metal valves, research is ongoing to assess
the need with the most recent generation of valves.
Key Words: valvular heart disease, VHD, stenosis, regurgitation, prosthetic
valve, bioprosthetic valve.
(Pharmacotherapy 2011;31(1):76–91)
OUTLINE
Overview of Hemodynamics
Diagnostic Testing and Evaluation
Aortic Valve Disease
From the Division of Cardiology, Department of
Medicine, University of Alberta, Edmonton, Alberta, Canada
(both authors).
For reprints, visit http://www.atypon-link.com/PPI/loi/phco.
For questions or comments, contact Tammy J. Bungard, B.S.P.,
Pharm.D., EPICORE Centre, University of Alberta, 220
College Plaza, Edmonton, Alberta, Canada T6G 2C8; e-mail:
[email protected].
Stenosis
Regurgitation
Mitral Valve Disease
Stenosis
Regurgitation
Patient Counseling
Bioprosthetic versus Prosthetic Valve
Monitoring and Follow-up After Surgery
Antithrombotic Therapy
Endocarditis Prophylaxis
Rheumatic Fever Prophylaxis
Conclusion
VALVULAR HEART DISEASE Bungard and Sonnenberg
Valvular heart disease is a commonly encountered
clinical condition that is not taught in most
undergraduate and graduate pharmacy programs,
leaving the practicing pharmacist without basic
knowledge to expand on and subsequently apply
to direct patient care. Unlike other areas of
cardiology in which thousands of patients are
recruited in multiple well-designed randomized
clinical trials, data assessing therapeutic
approaches in valvular heart disease are limited
and, when available, consist of retrospective case
series or observations. Our goal with this article
is to provide a basic overview of chronic valvular
heart disease, with emphasis on describing the
common conditions requiring surgery and the
available options, as well as common pharmacologic therapies used in this patient population.
Overview of Hemodynamics
The heart is a muscular pump with two atria
and two ventricles.1 Deoxygenated blood flows
through the inferior and superior vena cava into
the right atrium. It then flows across the
tricuspid valve into the right ventricle. From the
right ventricle, blood is pumped into the
pulmonary artery to the lungs, becomes
oxygenated, and flows through the pulmonary
vein into the left atrium. Once in the left atrium,
blood flows across the mitral valve into the left
ventricle. Blood is expelled across the aortic
Coronary
cusp
77
valve to the aorta and out to the rest of the body.
There are two types of valves within the heart:
semilunar and atrioventricular.2 The aortic and
pulmonic valves are the semilunar valves and
consist of three valve leaflets (Figure 1). The
mitral and tricuspid valves are atrioventricular
valves and differ in structure from the semilunar
valves. The atrioventricular valves consist of
leaflets—mitral having two leaflets (bicuspid)
and tricuspid having three leaflets—attached to
chordae tendinea, which are thin strands of
connective tissue that attach to papillary muscles
that attach to the ventricular wall (Figure 2).
With ventricular contraction, the papillary
muscles contract and prevent valves from
billowing back into the atria, maintaining valve
closure and preventing backleak.
The heart sound S1 (lub) signifies the nearly
simultaneous closure of the mitral and tricuspid
valves, with S2 (dub) being the closure of the
aortic and pulmonic valves. Accordingly, the
time interval between S 1 and S 2 is systole,
whereas the interval between S 2 and S 1 is
diastole. Systole usually is one third of the time
interval, with diastole taking two thirds of this
time.
The cardiovascular system is a closed loop
driven by changes of pressure (Figure 3).3 The
period of systole begins with isovolumic
contraction after closure of the mitral and
tricuspid valves (the aortic and pulmonic valves
Aortic
Annulus
Left atrium
Primary
chords
Papillary
muscles
Figure 1. The aortic valve (viewed from above) is a
semilunar valve and consists of three valve leaflets.
Figure 2. Mitral valve anatomy. The mitral valve is an
atrioventricular valve, which consists of two leaflets
(bicuspid) attached to the chordae tendineae, which are thin
strands of connective tissue that attach to papillary muscles
that attach to the ventricular wall. With ventricular
contraction, the papillary muscles contract and prevent
valves from billowing back into the atria, maintaining valve
closure and preventing backleak.
PHARMACOTHERAPY Volume 31, Number 1, 2011
78
Table 1. Murmurs with Common Forms of Valvular Heart Disease
Phase of
Valve Disease
Cardiac Cycle
Classic Findings on Physical Examination
Aortic stenosis
Systole
Midsystolic murmur that peaks in late systole and radiates to the carotids; single or
paradoxically split S2; low-amplitude, delayed carotid upstroke confirms presence
of severe aortic stenosis
Mitral stenosis
Diastole
Often early diastolic opening snap as thickened mitral valve “pops” open, followed
by low-pitched rumble of turbulent atrial inflow into left ventricle
Aortic regurgitation
Diastole
Hyperkinetic central and peripheral pulses; diastolic blowing murmur radiating from
aortic valve area down toward apex, S3 and S4 often heard as a manifestation of
volume or pressure load
Mitral regurgitation
Systole
Displacement of left ventricular apical impulse (indicates severe and chronic mitral
regurgitation with left ventricular dilation); murmur at mitral area heard throughout
systole, S3 indicating diastolic flow load usually present (does not indicate heart failure)
Mitral valve prolapse
Systole
Midsystolic click (high-pitched sound of short duration); may be followed by late
systolic murmur (medium-high pitch, loudest at the cardiac apex)
S2, S3, and S4 = second, third, and fourth heart sound, respectively.
are closed also). During this period, ventricular
pressure rapidly increases while the volume
remains unchanged. Once ventricular pressure
exceeds aortic (pulmonic) pressure, the aortic
(and pulmonic) valve opens and blood begins to
be ejected from the ventricle. Once systole is
finished, the pressure in the ventricle falls below
that in the aorta, the aortic (and pulmonic) valve
closes, and diastole begins. During diastole, left
ventricular pressure falls well below aortic
pressure, allowing coronary flow to reach even
the innermost layers of ventricular myocardium.
Pressure - Volume Tracings
Great V e ssel
P ressur e
3
Ventrr i cular
c ull ar
Pressure
2
1
Atrial
4
Time
Ventricular Systole
Isovolumic
Contraction time
Ventricular Diastole
Isovolumic
Relaxation time
End-diastolic volume
Volume
1
End-systolic volume
Figure 3. Pressure cycle of the heart. 1 = closure of mitral
and tricuspid valves (aortic and pulmonic also closed); 2 =
opening of aortic and pulmonic valves (mitral and tricuspid
closed); 3 = closure of aortic and pulmonic valves (mitral
and tricuspid closed); 4 = opening of mitral and tricuspid
valves (aortic and pulmonic closed).
Diastole consists of four phases: isovolumic
relaxation, rapid filling, diastasis, and atrial
contraction. 3 Isovolumic relaxation is a brief
phase where the aortic and mitral valves are
closed; the ventricular volume does not change,
but the pressure in this chamber declines
dramatically as ventricular muscle fibers relax.
The rapid filling phase begins with the opening
of the mitral (and tricuspid) valve, with pressure
in the ventricle falling below the atrium and
passive flow from atria to ventricles beginning.
Most ventricular filling (80%) occurs during this
phase, and once most of the atrial emptying has
occurred, the pressure difference between atria
and ventricles drops, and inflow slows. At this
point, minimal further filling of ventricles occurs,
and during this period of diastasis only about 5%
of ventricular filling occurs. Finally, if in normal
rhythm, atrial systole occurs and generates a
higher atrial pressure leading to resumption of
ventricular filling. In general, atrial systole
accounts for about 15% of the ventricular filling.
At onset of ventricular systole, ventricular
pressure exceeds atrial pressure, the mitral (and
tricuspid) valve closes, and diastole is complete.
Anomalies in valve function can be broadly
classified as stenosis (valve is too tight) or
regurgitation, sometimes termed insufficiency
(valve leaks).2 Both types of valve dysfunction
cause turbulent blood flow, which can be heard
on auscultation in the form of a murmur.
Screening for valve dysfunction is performed by
physical examination (including listening for
murmurs). Murmurs range from having no
functional clinical significance to being a
hallmark in identifying cardiovascular disease
VALVULAR HEART DISEASE Bungard and Sonnenberg
79
Table 2. Glossary of Hemodynamic Terms
Term
Definition
Afterload
Force against which the ventricle ejects blood once contraction of the muscle fibers begins
Annulus
Ring-like structure that forms the base of the heart valve and anchors the valve leaflets
Balloon
Procedure in which a narrow valve is stretched open by inflating a deflated balloon inside the tight
valvuloplasty
valve, usually introduced percutaneously through a catheter from percutaneous venous or arterial
access, thereby negating the need for open-heart surgery
Cardiac output
Quantity of blood pumped per unit of time (cardiac output = stroke volume x heart rate)
Concentric
Enlargement of the muscle mass inward, encroaching on inner chamber volume, with no outward
expansion of chamber (response to pressure overload)
hypertrophy
Commissure
Distinct area where the leaflets of the valve come together and insert into the annulus
Doppler
Technique for recording the flow of red blood cells through the cardiovascular system by means of
echocardiography
Doppler ultrasonography, either continuous wave or pulsed waves, generating either color images
that show areas of blood flow inside the regular sonogram (color Doppler) or spectral displays of the
blood flow directions and velocities from a focused part of the image. Doppler relies on detecting a
change in the reflected sound wave frequency when the sound beam hits moving blood. The degree
of frequency shift correlates with velocity of moving blood and can be used to calculate the driving
pressure creating the flow by means of the modified Bernouilli equation.
Eccentric
Enlargement of the chamber volume with elongation and some thickening of muscle fibers, with
hypertrophy
resultant increase in mass of the myocardium (response to volume overload)
Echocardiography
Examination of the heart by using ultrasonographic techniques to image structural and functional
abnormalities of the heart
Ejection fraction
Fraction of blood pumped out of the ventricle with each heart beat; a normal ejection fraction is
considered to be ≥ 60%, whereas significant systolic dysfunction is usually defined as an ejection
fraction ≤ 40%
Preload
Stretch imposed on the heart muscle due to ventricular and diastolic volume, or stretch imposed on
the heart muscle due to venous return emptying into ventricles from atria
Stenosis
Constriction or narrowing of a duct or passage
Transesophageal
Diagnostic test using an ultrasound device that is passed into the esophagus of the patient to create a
echocardiography
clear image of the heart muscle and other parts of the heart. A tube with a device called a transducer
is passed down into the patient’s throat and into the esophagus. The transducer directs ultrasound
waves into the heart, and the reflected sound waves picked up by the transducer are translated into
an image of the heart.
Valvotomy
Surgical cutting of a constricted cardiac valve to relieve obstruction
(Table 1). Tests to confirm or establish the
diagnosis include a variety of noninvasive tests
(electrocardiography, echocardiography, exercise
testing) and invasive tests (catheterization).4, 5
The definitions of many of these common
hemodynamic terms are provided in Table 2.
Diagnostic Testing and Evaluation
Cardiac imaging is commonly used for cardiac
diseases, and echocardiography (including
Doppler echocardiography) remains the test of
choice for valve disease.4, 5 No other imaging
modality has the extremely high frame rates
(typically 30–60 Hz) and resolution (0.5–1 mm)
that allows for accurate real-time imaging of fastmoving, thin valvular structures. Combined with
Doppler techniques, echocardiography can assess
most valve lesions accurately in terms of their
severity and etiology (Table 3). Doppler echocardiography assesses flow velocity by measuring
the change in ultrasound frequency when the
sound beam reflects off moving blood. Doppler
techniques create color images that show the area
of flow disturbance caused by stenosis or
regurgitation, and can also be used to estimate
the pressure gradients driving blood flow, thereby
allowing calculation of area of the valve. If
needed, transesophageal echocardio-graphy can
help assess valve morphology and function
extremely accurately without interference from
chest wall structures.
Cardiac magnetic resonance imaging (MRI)
and computed tomography are improving
resolution in assessing valves but cannot achieve
very high resolution real-time images, especially
if a major irregular rhythm disturbance does not
allow averaging multiple cardiac cycles to “sum
up” a representative image. 4 Cardiac MRI is
evolving to become the gold standard for assessment of ventricular volumes and function but
still is somewhat technically limited in assessing
severity of valve stenosis. It also has some difficulties with assessing valve regurgitation (especially in the presence of rhythm irregularities).4
Cardiac catheterization used to be the gold
80
PHARMACOTHERAPY Volume 31, Number 1, 2011
Table 3. Echocardiographic Findings with Valve Lesions
Valve Area
Pressure Gradient (mm Hg)a
2
Severity of Lesion
(cm )
Peak
Mean
Aortic stenosis
Mild
< 2.0
< 15
< 15
Moderate
1–1.5
< 64
< 40
Severe
< 1.0
> 64
> 40
b
Aortic regurgitation
Mild
Normal
Normal
Normal
Moderate
Normal
Variable
Variable
Severe
Normal
Mildly
Mildly
increased
increased
Mitral stenosis
Mild
< 2.0
Variable
<5
Moderate
1–1.5
Variable
5–10
Severe
< 1.0
Variable
> 10
b
Mitral regurgitation
Mild
Normal
Normal
Normal
Moderate
Normal
Normal
Normal
Severe
Normal
Mildly
May be mildly
increased
increased
Chamber Enlargement
None
None
None
None
Left ventricle
Left ventricle and left atrium
Left atrium, then right ventricle and right atrium
Left atrium, then right ventricle and right atrium
Left atrium, then right ventricle and right atrium
None
Left atrium and left ventricle may be enlarged
Left atrium and left ventricle, then right ventricle
and right atrium
a
Pressure gradients assume normal cardiac flow state and heart rates within normal range.
Use of ultrasensitive modern echocardiographic techniques has found that trivial valve regurgitation, especially mitral regurgitation, is
extremely common in healthy adults, often progressing to mild mitral or aortic regurgitation in many older patients in our population.
b
standard for assessing heart valve disease, but it
currently is almost exclusively reserved for
preoperative assessment of coronary arteries in
patients deemed to be high enough risk to have
developed coronary atherosclerosis.5 Very rarely,
invasive assessment of valve regurgitation or
stenosis is used to resolve discrepancies between
clinical impression and echocardiographic data.
Routine testing, such as chest radiography, may
be done to very crudely assess chamber size and
valve calcification, but this type of testing is best
reserved to confirm the presence of high left
heart filling pressures that present as varying
degrees of left heart failure. Further, electrocardiograms are routinely obtained at follow-up
visits to assess rhythm as well as offer nonspecific
information, such as ventricular enlargement.
Stress tests can be very useful to objectively
assess whether patients still have intact functional capacity, especially if there is concern that
patients have reduced their exercise gradually
without recognizing their subclinical cardiac
decompensation. However, stress testing should
not be performed if patients are believed to have
symptomatic severe aortic stenosis.
Aortic Valve Disease
Stenosis
Aortic stenosis is the most common form of
valvular disease.6 It most often occurs as a result
of calcification (a process described as being
similar to that of atherosclerosis) of the valve that
occurs with age, typically manifesting in patients
aged 60–90 years.5, 7 It may be evident earlier
(30–50 yrs old) among patients having a
congenitally malformed bicuspid aortic valve.
One to two percent of the population is born
with a bicuspid aortic valve, and this congenital
anomaly often leads to premature calcification of
the valve resulting in stenosis.8 Calcific aortic
stenosis occurs when solid calcium is deposited
within the cusps of the valve.9 In contrast, a very
rare cause of stenosis of the aortic valve may
occur by commissural fusion, typically in
patients with rheumatic heart disease who
already have mitral valve disease. Regardless of a
calcific or rheumatic etiology, aortic stenosis is
typically slowly progressive over decades, with
symptoms presenting only when the heart’s
ability to adapt has been exhausted.5
The increase in afterload as a result of the
stenotic aortic valve results in an increase in left
ventricle systolic pressure that is initially
compensated for quite well by the development
of concentric hypertrophy.4, 7, 9 This compensatory
response is initially appropriate and beneficial to
compensate for high intracavity pressures. The
hypertrophy, however, requires gene expression
that eventually is toxic to the myocardium. With
VALVULAR HEART DISEASE Bungard and Sonnenberg
time, this compensatory response increases
oxygen requirements of the myocardium, and
eventually the response is no longer able to
overcome increasing afterload nor compensate
for high left ventricular systolic pressures. As a
result, cardiac output declines and left atrial
enlargement to accommodate increased pressure
on the left side of the heart is evident. In a
critically narrowed aortic valve (critical aortic
stenosis), the heart cannot increase its output. A
vasodilator that decreases peripheral resistance
would therefore lead to potentially deadly
hypotension, since the heart would not be able to
increase cardiac output (blood pressure = cardiac
output x peripheral resistance).5, 7, 9 Concordantly,
reducing the preload excessively would also
decrease cardiac output, thus excessive
venodilators should be avoided. However,
treating marked hypertension may be beneficial,
since high aortic pressure only adds to the
already high afterload facing the left ventricle.
Symptoms, Prognosis, Monitoring
The symptoms of aortic stenosis consist of
angina, syncope, and heart failure or dyspnea,
almost exclusively in patients with severe aortic
stenosis.4, 7 With milder aortic stenosis, symptoms may occur only during states of exertion,
such as exercise, emotional stress, infection,
pregnancy, or atrial fibrillation with rapid
ventricular response rate. This prolonged latent
period with minimal symptoms, if any, carries
low rates of mortality and associated morbidity.
Aortic stenosis has an unpredictable rate of
progression. As such, depending on the degree
of stenosis, echocardiographic assessment is
indicated as little as every 5 years for patients
with mild aortic stenosis to as frequently as every
year or sooner in those with severe asymptomatic
aortic stenosis (especially if symptoms change).
As stenosis progresses, the cardiac output is
impaired at rest, resulting in the occurrence of
symptoms without exertion. Once patients
experience severe symptoms, survival is limited
to 2–3 years with a high risk of sudden death.10
Signs of severe aortic stenosis include a very
dampened downstream central pulse (low
volume, slowly rising carotid pulse) and a latepeaking systolic murmur.5
Treatment and Outcomes
Symptomatic patients with aortic stenosis have
exhausted the physiologic adaptations to severe
afterload from the mechanical obstruction of
81
aortic stenosis.5 There are no proven therapies
that improve the natural history or that are
known to alter the adaptative processes favorably.
Basic science work has suggested a similar
vascular atherosclerotic process occurs within the
valve leaflet, leading investigators to assess the
effect of lipid-lowering therapy in this disease
process.11, 12 Small, retrospective studies using
surrogate end points derived from echocardiography or cardiac computed tomography have
indicated benefit, but two randomized, prospective studies with clinical end points showed no
benefit.5, 13, 14 Many clinicians, however, believe
the major challenge with these data is that
patients are likely receiving statin therapy too
late in the disease process after the valve is
already heavily calcified.15
In theory, concomitant hypertension adds
further workload to the already afterloaded heart,
and many elderly patients have a stiff aorta with
increased impedance. Theoretically, it may help
to reduce blood pressure to nonhypertensive
levels, but the target blood pressure is not
known.16 In a randomized study, among patients
with symptomatic aortic stenosis without heart
failure, enalapril was well tolerated and improved
effort tolerance and reduced dyspnea. 17 This
study, however, provided follow-up for only 3
months and did not provide survival information.
However, excessive vasodilation is theoretically
lethal, since a major decrease in peripheral
vascular resistance would require a compensatory
increase in cardiac output to maintain aortic and
blood pressure (blood pressure = cardiac output x
mean vascular resistance), and there may be a
limit to how much more cardiac output can
increase with very tight aortic stenosis (fixed
cardiac output).
In a small study, patients already experiencing
pulmonary edema who were not treated with
diuretics or nitrates and had severe left
ventricular systolic dysfunction were given
intravenous nitroprusside to maintain mean
systemic blood pressure above 60 mm Hg.18 In
these patients, the elevated left heart filling
pressures decreased more toward normal, and
cardiac output improved. These patients,
however, were in frank heart failure and were not
treated with standard therapies known to confer
benefit. Thus, all patients with aortic stenosis
may not benefit from vasodilation, especially
given that standard heart failure therapies were
not used in this study.
Once patients have severe aortic stenosis with
symptoms, the only treatment is replacement of
82
PHARMACOTHERAPY Volume 31, Number 1, 2011
Table 4. Indications for Valve Surgery5
Indication for Surgery
Valve Disease
Aortic stenosis
Symptomatic, severe aortic stenosis
Asymptomatic aortic stenosis and abnormal exercise response (symptoms unmasked)
Severe asymptomatic aortic stenosis and high likelihood of rapid progression or long surgical
delays
Moderate or severe aortic stenosis if undergoing other open-heart surgery
Aortic regurgitation
Symptomatic, severe aortic regurgitation
Asymptomatic, severe aortic regurgitation and left ventricular systolic dysfunction (ejection
fraction < 50% or major left ventricular dilation)
Moderate-to-severe aortic regurgitation if undergoing other open-heart surgery
Mitral stenosis
Percutaneous mitral
Symptomatic NYHA functional classes II–IV, moderate-to-severe mitral stenosis, suitable valve
balloon valvuloplastya
Symptomatic NYHA functional classes II–IV, mild mitral stenosis, if evidence that mitral stenosis
is causing symptoms (high left atrial or pulmonary pressures during exercise), suitable valve
Asymptomatic moderate-to-severe mitral stenosis, with pulmonary hypertension, suitable valve
Atrial fibrillation with moderate-to-severe mitral stenosis, suitable valve
Symptomatic NYHA functional classes III and IV with less than ideal valve, but high surgical risk
Surgery
Repair (if possible) or replacement if symptomatic (NYHA functional classes III and IV)
moderate-to-severe mitral stenosis when percutaneous mitral balloon valvuloplasty is
unavailable or contraindicated
Mitral regurgitation
Symptomatic severe mitral regurgitation
Severe mitral regurgitation with new-onset atrial fibrillation
Asymptomatic severe mitral regurgitation with signs of left ventricular dysfunction
(ejection fraction 30–60%, or major left ventricular dilation) or pulmonary hypertension
Asymptomatic severe mitral regurgitation if > 90% chance of repair with experienced surgeon
Asymptomatic severe mitral regurgitation if undergoing other open-heart surgery
Consider if severe mitral regurgitation and secondary severe left ventricular dysfunction (ejection
fraction < 30%) if high chance of repair
Repair is recommended over replacement in majority with severe chronic mitral regurgitation
NYHA = New York Heart Association.
a
Ideally pliable, noncalcified valve, no major mitral regurgitation or left atrial clot.
the aortic valve (Table 4). 5 Debate exists
surrounding aortic valve replacement in the
asymptomatic patient.19, 20 Some are reluctant to
proceed with surgery given that 50% will
continue to be symptom free in 5 years, whereas
others are concerned about progression of the
disease with irreversible myocardial dysfunction.5
Among patients with left ventricular dysfunction,
the degree of reversibility of systolic function
depends on the extent to which the impaired
cardiac output is dependent on the increased
afterload imposed by the stenotic valve relative to
the degree of impaired myocardial contractility as
a result of increased pressure (i.e., the remodeling
within the ventricle). Although improved
symptoms and survival occur in both settings,
patients who have left ventricular dysfunction
due to exaggerated afterload may have complete
improvement in left ventricular function. 5 It
should be noted that in the setting of aortic
stenosis, age is not a contraindication for
surgery—the very elderly have similar outcomes
to those of age-matched controls.5, 19, 20 Recently,
percutaneously delivered balloon-expandable
bioprosthetic (tissue) valves were implanted in
patients too sick to undergo open-heart valve
replacement. It is still too early, however, to
know whether this technique, compared with
palliative drugs, will have better outcomes, and
whether it will ever replace open-heart surgical
aortic valve replacement.21
Regurgitation
Aortic regurgitation is either due to abnormal
valve leaflets (congenitally malformed bicuspid
aortic valve, or due to age-related degeneration,
endocarditis, or rheumatic fever) or from a
dilated root of the aorta pulling normal leaflets
apart (due to hypertension, collagen vascular
disorder, Marfan’s syndrome, or idiopathic
dilation of the aorta).22 Like aortic stenosis, the
onset of aortic regurgitation is gradual and
progression continues over decades.5, 22
With aortic regurgitation, end diastolic volume
increases in the left ventricle due to a progressively increasing retrograde flow of blood across
the aortic valve.5, 19 The left ventricle responds to
VALVULAR HEART DISEASE Bungard and Sonnenberg
this volume load by increasing its compliance to
accept a larger volume without a major filling
pressure increase. As aortic regurgitation worsens,
the left ventricle has to eject increasingly large
volumes in order to ensure enough net forward
output. This high output into the relatively stiff
aorta raises aortic pressure and thus left
ventricular afterload. The combined volume and
pressure overload contribute to dramatic
hypertrophy, and eventual left ventricular systolic
dysfunction. Earlier in the disease, the systolic
dysfunction is primarily related to excess
afterload, and subsequently full recovery of
ventricular function is achievable with correction
of the aortic regurgitation. Uncorrected,
alterations in ventricular chamber size (spherical
geometry) and reduced myocardial contractility
predominate as the cause of systolic dysfunction
over the excessive afterload. Once these changes
have occurred, left ventricular recovery and
survival benefit may not occur after correction of
the aortic regurgitation.5
Symptoms, Prognosis, and Monitoring
Aortic regurgitation has a gradual onset.5, 22
The left ventricle has tremendous reserve dealing
with aortic regurgitation volume and afterload,
leaving many patients asymptomatic for decades.
However, more than 25% of patients who die or
develop systolic dysfunction do so before the
onset of warning symptoms, emphasizing that
thorough patient questioning is insufficient in
serial evaluation of asymptomatic patients. 5
Routine echocardiography is recommended as
little as every 2–3 years, and often more
frequently (at least annually with severe aortic
regurgitation 5 and perhaps every 4–6 mo if
alterations in left ventricular shape or function
are present).
Once left ventricular dysfunction is evident,
patients are likely to have symptoms begin at a
rate of about 25%/year, and the disease progresses
more rapidly.22 Symptoms are typical for that of
left-sided heart failure, although angina can also
occur due to higher oxygen demands from the
workload or left ventricular hypertrophy. After
experiencing symptoms, most patients will
require surgical aortic valve replacement, as with
aortic stenosis (Table 4). Untreated, mortality
increases dramatically with symptoms of angina
(> 10%/yr) and heart failure (> 20%/yr).5, 22
Treatment
Vasodilator therapy can reduce the hemodynamic
83
burden in some patients by reducing systemic
vascular resistance and enhancing forward flow
while reducing regurgitation driving pressure and
lowering the regurgitant volume and left
ventricle afterload.5, 23, 24 Although earlier data
suggested that nifedipine delayed the need for
aortic valve replacement in patients with normal
left ventricular function and asymptomatic severe
aortic regurgitation, 25 a randomized trial
comparing nifedipine 20 mg every 12 hours with
enalapril 20 mg/day and placebo revealed no
benefit to vasodilator therapy either in terms of
slowing the need for surgery or reducing left
ventricular volume loading or severity of
regurgitation.23 It may be, however, that these
randomized trials lacked large enough sample
sizes to have statistical power to detect true
benefits or perhaps that there was an inadequate
drug effect to achieve necessary vasodilation.24
Thus, vasodilators are only recommended in
severe aortic regurgitation for the following
circumstances: long-term treatment of those
deemed poor candidates for surgery because of
cardiac or noncardiac factors, short-term use to
improve the hemodynamic profile in preparation
for aortic valve replacement among those with
severe heart failure symptoms or severe left
ventricular dysfunction, and to prolong the
compensated phase of asymptomatic patients
with normal systolic function.5 Clearly, surgery
is the only known corrective option (Table 4), as
there is no certainty that vasodilators dramatically
change the natural history of this valve problem.
Mitral Valve Disease
Stenosis
Mitral stenosis is almost exclusively caused by
rheumatic heart disease, an inflammation of all of
the endocardium, myocardium, and pericardium in
response to a group A Streptococcus infection.5, 26
Several years after the infection, the initial damage
predisposes to leaflet thickening, commissural
fusion, and chordal shortening and fusion.5, 27
After the acute episode of rheumatic fever, a slow
stable course, with a latent period of 20–40 years,
ensues, followed by progressive acceleration later
in life. The mean onset of progression is 50–60
years of age, and it is twice as likely in women.
The more group A streptococcal infections,
however, the faster the process.
With mitral stenosis, blood flow relies on the
transmitral pressure gradient. 5, 22, 27 The left
atrium enlarges as afterload increases with
progressive mitral stenosis, and this leads to an
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PHARMACOTHERAPY Volume 31, Number 1, 2011
increase in pressure in the pulmonary venous
circulation. Eventually, the right ventricle bears
the burden of propelling blood across the mitral
valve. The right ventricle becomes compromised
by afterload imposed on it by high left atrial
pressures that secondarily causes pulmonary
vasoconstriction and will eventually lead to fixed
pulmonary hypertension. Furthermore, due to
the increase in left atrial pressure and dilation of
the left atrium, 30–40% of patients with mitral
stenosis will develop atrial fibrillation.22 The
development of atrial fibrillation is correlated
with the severity of mitral stenosis and left atrial
pressure. With atrial fibrillation in the setting of
mitral stenosis, systemic embolization may occur
at much higher rates than in nonvalvular atrial
fibrillation, 20–30%/year. 22 About 65% of all
embolic events occur within the first year of the
onset of atrial fibrillation.19, 22
Symptoms, Prognosis, and Monitoring
The symptoms of mitral stenosis are due to the
high left atrial pressure needed to drive blood
across the tight valve, mimicking left-sided heart
failure (without any actual left ventricular
failure).5, 19, 22 As with aortic stenosis, symptoms
early in mild mitral stenosis are elicited by
exertional states. Later, atrial fibrillation may
cause dramatic worsening of heart failure
symptoms (tachycardia and loss of atrial “kick”
helping to drive blood across the valve), and
eventual right-sided heart failure (edema, fatigue,
ascites, and abdominal distension) may follow.
The 10-year survival rate for patients having
either mild or no symptoms with mitral stenosis
is 80%.22 All patients with mitral stenosis should
be assessed at least annually, with a history,
physical examination, and electrocardiogram.5
Routine follow-up with echocardiography is
necessary, and its frequency is dictated by the
severity of clinical and echocardiographic
findings (ranging from yearly or more often if
symptoms develop to as little as every 5 yrs).
From the onset of symptoms, it is typical for a
decade to pass before the occurrence of disabling
symptoms. Once limiting symptoms are present,
the 10-year survival rate declines to 0–15%. Data
reveal that death in untreated patients is often
due to progressive heart failure (60–70%),
systemic embolism (20–30%), pulmonary
embolism (10%), or infection (1–5%). 5, 19, 22
Furthermore, once patients experience severe
pulmonary hypertension, mean survival is less
than 3 years.
Treatment
Given that a mechanical narrowing of the
mitral valve orifice is central to all pathology
related to this disease process, no medical
therapy will provide complete resolution.5, 19, 27
Hydrochlorothiazide or low-dose furosemide
(gentle diuresis) may help patients with high
back-pressure from the tight mitral stenosis. In
addition, heart rate slowing is critical to help
increase the percentage of time the heart spends
in diastole, allowing more time for left atrial
emptying into the venticle (tachycardia actually
causes the heart to spend longer in systole than
in diastole, dramatically raising the mitral
pressure gradient needed to push the same flow
through the heart). ␤-Blockers and rate-slowing
calcium channel blockers remain the backbone of
rate-slowing therapy in these situations. In atrial
fibrillation, adding digoxin may further help
heart rate slowing, whereas warfarin is crucial to
decrease the otherwise extremely high embolic
risk for patients with mitral stenosis and atrial
fibrillation. 28 Attempting to prevent atrial
fibrillation with antiarrhythmics is theoretically
attractive but remains limited by the relative lack
of effectiveness of these drugs to fully suppress
atrial fibrillation. Even in patients with
nonvalvular atrial fibrillation, treatment with the
most effective antiarrhythmic amiodarone had an
incomplete success rate of only 70% of patients
after 1 year.29 In addition, major concerns about
toxicity (including potentially lethal
proarrhythmia) remain for almost all
antiarrhythmics. Although dronedarone might
not have these potential mortality concerns, there
are worries about its relative lack of effectiveness
even in nonvalvular atrial fibrillation.30
Ultimately, mechanical intervention is required
for patients with moderate mitral stenosis (Table
4). The options include percutaneous mitral
balloon valvotomy or surgical mitral valve repair
or replacement.5, 19 With balloon valvotomy, a
catheter is inserted into the femoral artery and a
deflated balloon is pushed across the mitral
valve. The end of the catheter contains the
hourglass-shaped balloon that is inflated across
the valve orifice and “cracks open” the valve,
usually doubling the valve area with a 50–60%
decline in the transmitral gradient. This
procedure, however, is technically challenging,
and medical centers that perform large volumes
of this procedure have better success with fewer
complications.5 Surgical or open commissurotomy is the surgical division of fibrous chords or
VALVULAR HEART DISEASE Bungard and Sonnenberg
commissures of the mitral valve to relieve the
stenosis. If neither balloon nor surgical mitral
valve repair is possible, then mitral valve
replacement remains the final option.31
In general, the type of intervention performed
takes into account the morphology of the mitral
valve apparatus, patient comorbidities, and
center-specific practices and expertise.5, 19 The
timing of the procedure is dictated by the severity
of the disease. 5, 19 Outcomes of mitral valve
replacement surgery correlate directly with age.
Morbidity and mortality rates are less than 5% for
a young healthy person and as high as 10–20% in
older patients with concomitant medical
problems or pulmonary hypertension. 19 Both
younger and older patients have lower operative
mortalities and superior outcomes with mitral
valve repair compared with replacement. 32
Preservation of the subvalvular apparatus, as
done with repair and not always feasible with
replacement, aids in maintaining left ventricular
function.5 This, however, is particularly unlikely
in the setting of rheumatic mitral stenosis.5
Mitral Regurgitation
Chronic mitral regurgitation is commonly
caused by the syndrome of mitral valve prolapse
([MVP] hypermobile “floppy” chordae or leaflets
that cause leakage), distorted papillary muscles
from myocardial damage due to coronary artery
disease (so-called ischemic mitral regurgitation),
or from simple dilation of the left ventricle
pulling apart the mitral apparatus (functional
mitral regurgitation). 5, 33–35 Less commonly,
rheumatic heart disease often combined with
stenosis may cause mitral regurgitation. 5, 33
Whatever the initial cause, mitral regurgitation
often leads to progressive enlargement of the left
ventricle, with the ventricle becoming more
spherical, causing more papillary muscle
displacement and further worsening mitral
regurgitation (mitral regurgitation begets mitral
regurgitation). 33 In general, ischemic mitral
regurgitation is prognostically worse that
nonischemic mitral regurgitation.35, 36
Mitral valve prolapse, a nonischemic form of
mitral valve disease, is common in the general
population, affecting 1–2.5%. 5, 34, 37 Although
MVP is typically benign, because of its prevalence
in the population, it is the leading cause of mitral
regurgitation today.34 In most of these patients,
MVP has no effect on their life expectancy, but
rarely MVP can significantly affect morbidity and
mortality. With MVP, the leaflet(s) billows into
85
the left atrium (must be > 2 mm above the mitral
annulus).5, 34
Regardless of the cause of chronic mitral
regurgitation, the hemodynamic compensation
and progression are the same. 5, 34, 38 Ejection
from the left ventricle into the low pressure and
generally very compliant left atrium is easier than
normal forward ejection through the aortic valve,
and provides a low afterload. Because of the
large amount of left ventricle ejection lost back
into the left atrium, both the left atrium and left
ventricle must have substantially higher filling
(preload) to maintain adequate net forward
output. Thus, in the setting of normal
myocardial function, the ejection fraction should
appear above normal. Once mitral regurgitation
becomes severe, over 50% of the left ventricular
output regurgitates backward, requiring doubling
of left ventricular output, and thus leads to left
ventricular and left atrial dilation with eccentric
hypertrophy. This increase facilitates a greater
stroke volume with each ventricular contraction,
thereby allowing sufficient cardiac output to
allow some patients to remain asymptomatic,
even with vigorous exercise. Patients having
mild-to-moderate mitral regurgitation remain
asymptomatic for several years, having little to
no hemodynamic compromise. However,
continued volume overload eventually results in
left ventricular contractile dysfunction, perhaps
because the same factors that promote dilation
and hypertrophy are also, in the long term, toxic
to myocardium.39 Due to the favorable loading
conditions, however, ejection fractions are often
maintained within the low normal range
(50–60%), despite substantial muscle damage.
Allowed to progress, pulmonary hypertension
will develop, conferring a poor prognosis.5, 19
Symptoms, Prognosis, and Monitoring
The symptoms of mitral regurgitation are
consistent with left-sided heart failure (e.g.,
pulmonary congestion).5, 36 After severe mitral
regurgitation is detected, patients are likely to
develop symptoms or have left ventricular
dysfunction within 6–10 years.5, 36 With mitral
regurgitation, assessing a patient’s exercise
tolerance or occurrence of or change in symptoms is crucial given the insidious progression of
this disease. Monitoring with echocardiography
for those with moderate-to-severe mitral
regurgitation should occur either annually or
sooner if symptoms change, with ongoing
assessment of ventricular dimensions and
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PHARMACOTHERAPY Volume 31, Number 1, 2011
volumes given that the ejection fraction typically
is above normal. Correction of mitral regurgitation should be considered before substantial
decline in left ventricular function (ejection
fraction < 60%) as progressive deterioration in
myocardial function confers a poorer prognosis.
Prognosis worsens as the disease ensues and
manifests with pulmonary hypertension.5, 19, 33
Treatment
Differentiation between ischemic and
nonischemic mitral regurgitation is important in
the medical management of this population.5, 35
Those with mitral regurgitation due to dilated or
ischemic cardiomyopathy may benefit from
pharmacologic agents reducing preload given the
pathophysiology of this disease process.5, 33 If left
ventricular dysfunction is evident, standard
treatments for heart failure are beneficial in
reducing the severity of functional mitral
regurgitation. 5, 37, 40 For patients having
nonischemic mitral regurgitation, no widely
accepted recommendations have been made
surrounding medical management. 5 Once
patients develop symptoms, however, surgical
options should be considered for both ischemic
and nonischemic mitral regurgitation, even if left
ventricular function is normal.5, 19
Three types of operations for mitral valves in
the setting of mitral regurgitation are used:
mitral valve repair, mitral valve replacement with
preservation of part or all of the mitral apparatus,
and mitral valve replacement with removal of the
mitral apparatus.5, 19, 38 In general as with mitral
stenosis, mitral valve repair confers lower
operative mortality and superior late outcomes in
comparison with mitral valve replacement.5, 37, 38
The mitral apparatus consists of chordae
tendineae attaching the cusps of the valve to the
papillary muscles that are part of the left
ventricular wall (Figure 2). This apparatus is an
integral part of the left ventricle, important in
maintaining normal shape, volume, and function.
As such, removal of this apparatus (as seen with
many older valve replacements) leads to poorer
postoperative left ventricular function and
survival compared with leaving it intact. 5, 33
Repairing the mitral valve, however, requires that
the valve morphology is suitable and that the
appropriate surgical skill and expertise are
available; these procedures are technically
challenging, usually most often for MVP than for
other causes of mitral regurgitation.5, 37, 38 When
replacing the mitral valve is mandatory, surgeons
will always consider preserving the chordae
tendineae (if possible), as this procedure tends to
relieve symptoms and maintain preoperative left
ventricular function. Replacing the mitral valve
with removal of the mitral apparatus is only done
when absolutely necessary—that is, in situations
in which the native preoperative morphology
simply cannot be spared, as in patients with
rheumatic disease.5 If possible, in patients with
rheumatic mitral regurgitation, artificial chordal
reconstruction is done to preserve the mitral
apparatus.5
With ischemic mitral regurgitation, concomitant
surgery may be indicated for coronary revascularization, as data show that correction of only the
valve anomaly by means of ring annuloplasty
offers short-term benefit.5, 19, 33, 35 Many patients
continue to have mitral regurgitation as the
ventricle continues to remodel after the procedure. Patients with ischemic mitral regurgitation
have poorer prognoses than those with nonischemic mitral regurgitation and have a greater
rate of mitral regurgitation recurrence after valve
repair.35, 36
In contrast to ischemic mitral regurgitation,
those with MVP tend to have exceptional
long-term survival beyond 10 years and up to 20
years after surgical repair of the valve.5, 32 The
indications for surgery for MVP and mitral
regurgitation parallel those for other forms of
severe ischemic mitral regurgitation (Table 4).5
Patient Counseling
Patients with any of the four valve lesions
discussed should be informed of the slow yet
variable progression of their disease.5 With MVP,
recognition of a typical benign prognosis, with
encouragement to have a normal lifestyle, should
be emphasized.5 Routine questioning surrounding
changes in symptoms, most likely to occur
initially with increased activity or exercise, should
be done in patients with any type of valvular
heart disease to serve as a surrogate for disease
progression. Patients should be encouraged to
report deterioration or changes in their symptoms, as objective reassessment through echocardiography may be warranted. Specific symptoms for each lesion are identified in Table 5.
With mitral stenosis, the pharmacist should be
alerted to the increased likelihood for development of atrial fibrillation and be prepared to
discuss concordant symptoms of atrial fibrillation
with the patient. In contrast, with mitral regurgitation (and aortic regurgitation) patient
VALVULAR HEART DISEASE Bungard and Sonnenberg
87
Table 5. Topics for Counseling of Patients with Valvular Heart Disease
Valve Lesion
Danger Symptoms
Exercise Recommendations
Aortic stenosis
Angina, syncope, dyspnea
Asymptomatic-to-mild disease: unrestricted exercise
(on exertion, later frank heart
Moderate-to-severe disease: avoid high-intensity or competitive
failure with orthopnea or PND)
sports, consider exercise testing before beginning exercise program
Aortic
Dyspnea (on exertion,
Asymptomatic, mild, or moderate disease with normal left ventricular
regurgitationa
shape and function: encourage exercise, including competitive
orthopnea, PND), angina,
palpitations
sports
Severe disease: limit exercise to mild or moderate aerobic activitiesb
Mitral stenosis
Dyspnea (on exertion,
Symptom-limited exercising
orthopnea, PND)
Avoid tachycardia-provoking situationsc
If moderate-to-severe disease: avoid competitive sports
Mitral
Dyspnea (on exertion,
Symptom-limited exercisingb
regurgitationa
orthopnea, PND)
If moderate-to-severe disease: avoid competitive sports
PND = paroxysmal nocturnal dyspnea.
a
Symptom-related progression is often delayed, imparting the importance of serial objective assessment of valve lesion.
b
Activities increasing aortic pressure (i.e., isometric exercises such as yoga or weight lifting) are strongly discouraged due to the likely increase
in the aortic regurgitation driving pressure.
c
Sudden onset of pulmonary edema may occur in an asymptomatic patient if there is rapid onset of atrial fibrillation; hence, patients should be
counseled to seek medical attention if shortness of breath develops, as this could be life-threatening.
Table 6. Characteristics of the Ideal Valve Design42
Factor
Ideal Valve
Flow
Unobstructed, laminar flow
Comments
Subsequent generations have improved flow across the valve
Gradient across
valve
Low, to not cause stenosis or
damage blood cells
Rigid leaflets interact with blood cells
Inert material
Avoid interaction with blood
components (i.e., activation of
clotting cascade or shear force
activation of platelets)
Avoid infection
Tissue valves are more biocompatible compared with prosthetic
Newer materials, such as pyrolytic carbon, may be superior in
minimizing interaction with blood components and minimizing
infection
Durability
Strong
Metal valve components do not wear out, tissue valves will
eventually wear out
education surrounding the insidious progression
is paramount and must encompass a conscious
effort to gauge the patient’s baseline exercise
tolerance in order to allow detection of subtle
changes from a patient’s baseline. Various
recommendations surrounding exercise for each
valve lesion are included in Table 5. 5, 41
Concordant with recommendations for specific
valve lesions, any patient taking anticoagulants
(e.g., for atrial fibrillation or metal heart valves)
should avoid contact sports.41
Bioprosthetic versus Prosthetic Valves
In the 1960s with the introduction of cardiopulmonary bypass, the ability to replace valves
with good outcomes became evident. 5, 19, 34
Worldwide, approximately 300,000 valve replace-
ments are performed annually.19 Characteristics
of the ideal valve are described in Table 6. 42
There are two types of valves for implantation:
bioprosthetic (tissue) valves and prosthetic
(mechanical, metal) valves (Table 7). 5, 42, 43
Bioprosthetic valves are heterografts derived from
either a porcine or bovine source.43 Mechanical
valves are composed of plastic and metal
components. The decision to implant a tissue
versus a metal prosthetic valve is made in
conjunction with the patient, considering life
expectancy and ability or willingness to accept
lifelong anticoagulation therapy. 5, 19, 42, 43 Overall,
bioprosthetic valves are less thrombogenic and
hence do not mandate lifelong anticoagulation
therapy; however, the trade-off is that they are
less durable than metal valves.
Bioprosthetic valves are preferred in situations
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PHARMACOTHERAPY Volume 31, Number 1, 2011
Table 7. Bioprosthetic and Prosthetic Valves
Type of Valve
Description
Bioprosthetic
Trileaflet tissue (bovine and porcine)
(tissue)
Nonstented (free porcine aortic root)
Trade Namea
Carpentier-Edwards, Hancock, Medtronic Mosaic
Freestyle
Prosthetic
(mechanical, metal)
First generation
Second generation
Third generation
Potential
Starr-Edwards
Bjork-Shiley, Medtronic-Hall, Omnicarbon
St. Jude, Carbomedic, Edwards-Duromedics
On-X valve
Ball and cage
Single tilting disk (monoleaflet)
Bileaflet tilting disk
Bileaflet tilting disk
a
Manufacturers are as follows: Carpentier-Edwards: Edwards Lifesciences, Irvine, CA; Hancock: Medtronic, Minneapolis, MN; Medtronic
Mosaic: Medtronic; Freestyle: Medtronic; Starr-Edwards: Edwards Lifesciences; Bjork-Shiley: Pfizer, New York, NY; Medtronic-Hall: Medtronic;
Omnicarbon: Medical CV, Inver Grove Heights, MN; St. Jude: St. Jude Medical, St. Paul, MN; Carbomedic: Carbomedics Inc., Austin, TX;
Edwards-Duromedics: Baxter Healthcare Corp., Edwards Division, Santa Ana, CA; On-X valve: On-X Life Technologies, Inc., Austin, TX.
of limited life expectancy (< 10–15 yrs) given
their limited durability.5, 19, 43 Native valves have
the unique ability to become rigid under stress
(when they close) but become very pliable when
they need to open, and, as living tissue, can selfrepair.2 Unfortunately, nonliving tissue cannot be
made to mimic this alternating rigidity and
pliability. Thus, eventually tissue valves degenerate,
especially in younger patients with presumably
higher cardiac output across the valves. Ten-year
failure rates exceed 42% when implanted in
patients younger than 40 years.43 In contrast,
patients older than 70 years have a 10% chance
of the tissue valve failing in 10 years, and 50%
are still functioning adequately at 15–17 years.43
Tissue valves have reduced thrombogenicity;
thus, patients do not have to receive lifelong
anticoagulation therapy. As such, bioprosthetic
valves should be considered in patients unable or
unwilling to take vitamin K antagonists (e.g.,
patients desiring pregnancy, those with
contraindications to warfarin therapy).
Mechanical metal valves should be considered
in patients whose life expectancy exceeds 10–15
years and who are able and willing to take
vitamin K antagonists.19, 43 Three generations of
mechanical valves have been marketed, with each
subsequent generation having improvements in
flow patterns across the valve and reduced
thrombogenicity (Table 7).42–44 Earlier generation
valves (ball and cage) encouraged more lateral
blood flow, whereas recent ones (bileaflet) have
more central blood flow that parallels the
physiologic pattern.42 With improved blood flow
and synthetic materials, the rates of thromboembolic complications for later generations of
valves are reduced. Given this, most patients
having metal valves implanted today receive a
bileaflet valve. To date, in North America, all
patients having metal valves implanted have
required full-intensity warfarin therapy.42
In January 2006, the On-X prosthetic valve
(On-X Life Technologies, Inc., Austin, TX) was
approved for use based on an investigational
device exemption.45 This valve is promoted as
having superior material (pure pyrolytic carbon)
and design (inlet flares mimicking the native
valve) and is purported to have a better life span
(i.e., lifetime) and fewer complications.45 The
Prospective Randomized On-X Valve Anticoagulation Trial (PROACT) is under way.46 This trial
is recruiting and will assess the ability to use
aspirin alone or lower-intensity warfarin therapy
(international normalized ratio [INR] target
1.5–2.0) against standard of care with 5 years of
follow-up. An intermediate follow-up report of
European patients receiving aortic (184 patients)
or mitral (117 patients) On-X valves having an
INR range of 3.0–4.5 reported rates of
thromboembolism of 0.88% and 1.76%/patientyear, respectively. 47 Given the target of anticoagulation, these results are comparable to
current valve options. We will, however, await
data from PROACT. If positive, these results
have the potential to revolutionize the care of
patients with prosthetic heart valves.
Monitoring and Follow-up After Surgery
Both bioprosthetic and metal valves require
regular postoperative follow-up. 5 A baseline
echocardiogram should be obtained within the
first half year after implantation to ensure no
early valve complications are evident (e.g.,
undersized valve leading to residual stenosis, or
valve dysfunction with major residual regurgitation). Fortunately, mechanical failure of metal
valves is rare, especially in the first years after
surgery. Mechanical failure accelerates especially
VALVULAR HEART DISEASE Bungard and Sonnenberg
89
Table 8. Antithrombotic Therapy for Bioprosthetic and Prosthetic Valves49
Duration of Antithrombotic Therapy and
Indication
INR
Other Treatment Options
Bioprosthetic (tissue) valves
Mitral valve
2.0–3.0
3 mo, then aspirin 50–100 mg/day
Aortic value
NA
Aspirin 50–100 mg/day
Atrial fibrillation or left atrial thrombus
2.0–3.0
Until risk of left atrial thrombus is gone
during surgery
(often indefinite)
2.0–3.0
> 3 mo
History of systemic embolism
Additional thromboembolic risk factors
2.0–3.0
Long term; add aspirin 50–100 mg/day
(atrial fibrillation, hypercoagulable
if history of atherosclerotic vascular
state, or low ejection fraction)
disease (avoid if age > 80 yrs and history
of gastrointestinal bleed)
Prosthetic (mechanical, metal) valves
Mitral valve
Aortic valvea
Additional thromboembolic risk factors
(atrial fibrillation, hypercoagulable
state, low ejection fraction, history of
atherosclerotic disease)
Systemic embolism despite a therapeutic
INR
2.5–3.5
2.5–3.5
2.5–3.5
Long term
Long term
Add aspirin 50–100 mg/day unless
age > 80 yrs or history of gastrointestinal
bleed
2.5–3.5 or
3.0–4.0
Add aspirin 50–100 mg/day, or up-titration
only
INR = international normalized ratio; NA = not applicable.
a
For aortic bileaflet valve or Medtronic-Hall monoleaflet valve (Medtronic, Minneapolis, MN) and normal sinus rhythm
and no left atrial enlargement, INR range is 2.0–3.0.
in bioprosthetic values after about 10 years, and
annual echocardiography should be performed
starting at 7 years in patients with a bioprosthetic
value. Even metal valves can develop mechanical
failure if scar tissue (pannus) starts to grow and
encroach on the valve orifice, creating prosthetic
stenosis or regurgitation. The rate of prosthetic
valve infective endocarditis is similar for both
types of valves (1%/yr).48 In addition, the annual
thromboembolism rate with bioprosthetic values
is similar to that with fully anticoagulated metal
valves at 1–2%. 49 Thus, despite the fact that
bioprosthetic valves do not require long-term
anticoagulation (although many surgeons require
anticoagulation in patients for the first 3 mo),
both types of valves can be associated with
potentially serious embolism. Patients should
therefore be regularly followed by a specialist to
monitor valve function.
Antithrombotic Therapy
The risk of thromboembolism in patients with
valve replacements is dependent on the position of
the valve (aortic or mitral), the type of valve
(bioprosthetic or prosthetic), as well as other
clinical and echocardiographic characteristics.5, 49, 50
Overall, mitral valves are more thrombogenic
than aortic valves because of the flow patterns
around the valve and the increased likelihood of
the development of atrial fibrillation with mitral
valve disease.49, 50 Concomitant risk factors, such
as atrial fibrillation, low ejection fractions, and
history of atherosclerotic disease, often encompass
an indication for concomitant aspirin therapy.49
An overview of current recommendations for
antithrombotic therapy in patients with bioprosthetic and metal valves is provided in Table 8.49
Endocarditis Prophylaxis
Infective endocarditis is defined as an infection
of the endocardial (inside) layer of the heart,
which usually affects the heart valves.5, 48 Both
native and artificial valves may be affected. The
pathophysiologic process occurs initially as a
result of turbulence or trauma to the endothelial
surface of the heart that encourages platelet and
fibrin deposition with resultant formation of
nonbacterial thrombotic endocardial lesions.
Subsequently, transient bacteremia may lead to
the seeding of these lesions with bacteria
adhering and multiplying within them, creating
an infective vegetation.48 As such, consideration
should be given to antibiotic prophylaxis for
procedures (primarily dental) exposing patients
with valvular heart disease to systemic infections.
For dental procedures, this encompasses any
procedure likely to cause gingival bleeding or
penetration of the mucosa.5 When these occur,
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PHARMACOTHERAPY Volume 31, Number 1, 2011
antibiotic prophylaxis is indicated for patients
with prosthetic heart valves or valve repairs
containing prosthetic material.5 A single dose of
amoxicillin 2 g is recommended for adults;
clindamycin 600 mg is an alternative for those
with penicillin allergy.48
Antibiotic prophylaxis is not necessary for
procedures that do not perforate the mucosa,
such as transesophageal echocardiography,
diagnostic bronchoscopy, esphagogastroscopy, or
colonoscopy. 5, 48 Furthermore, prophylaxis is
unnecessary for all patients with native valve
disease (whether stenosis or regurgitation), MVP,
innocent murmurs, and those with abnormal
echocardiographic findings without an audible
murmur. According to the American College of
Cardiology–American Heart Association
guidelines, only patients with prosthetic valves,
previous endocarditis, unrepaired complex
cyanotic heart disease, or heart transplant
recipients with major valve lesions should receive
endocarditis prophylaxis.5, 48
Rheumatic Fever Prophylaxis
Rheumatic fever is a systemic inflammatory
disease that may occur weeks after an untreated
infection with group A Streptococcus, as with
“strep throat” or scarlet fever, and is believed to
be caused by antibody cross-reactivity. 5, 26
Typically, the inciting infection occurs early in
life (ages 5–15 yrs) and manifests later in life
with clinical sequelae. Valvular heart disease
occurs with time, with repeated inflammation
with fibrous resolution, causing valve leaflet
thickening, commissural fusion, and shortening
and thickening of the tendinous cords. As such,
prompt recognition and treatment are paramount
for the primary episode, whereas for those having
a history of rheumatic fever (including those
with mitral stenosis), secondary antistreptococcal
prophylaxis is warranted for recurrent fever. 5
Various regimens that are penicillin based are
appropriate for these purposes.5
Conclusion
Although pharmacists commonly encounter
patients with valvular heart disease, the disease is
often not well understood and subsequently
patients are denied reinforcement of pertinent
information. Understanding the cardiac cycle
and the valve anomaly allows a logical progression of consequences to the cardiovascular
system. With this understanding, pharmacists
can effectively counsel patients surrounding
disease progression and self-monitoring, use of
vasodilator therapy, and prophylaxis for
endocarditis and rheumatic fever. Where
appropriate, important therapies (e.g., for atrial
fibrillation, heart failure, hyperlipidemia) to
reduce overall risk should be implemented in this
patient population. Knowledge of the differences
between bioprosthetic (tissue) values and
prosthetic (mechanical, metal) valves is
important in the provision of antithrombotic
therapy, and this area continues to be evaluated
in clinical trials.
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