1. health and fitness
2. disease

REVIEW
M A R I O J. GARCIA M D
Director, Echocardiography Laboratory;
Cardiovascular Imaging Center,
Department of Cardiology, Cleveland Clinic
Diastolic dysfunction and heart failure:
Causes and treatment options
ABSTRACT
Diastolic dysfunction is the underlying problem in one third
of patients with heart failure, but it is still not well
understood. Carefully excluding other causes of heart
failure arid recognizing indicators of diastolic dysfunction
on invasive and noninvasive tests are important in
establishing the diagnosis and in guiding therapy.
KEY POINTS
Left ventricular relaxation and stiffness and left atrial
function are the most important factors acting together to
maintain adequate cardiac output under normal filling
pressure.
Echocardiography is the most important tool for the
diagnosis of diastolic heart dysfunction. It is portable, safe,
and excludes other causes of heart failure, such as valvular
disease.
Diuretics can be used to reduce volume overload, but
caution is advised, as aggressive diuresis decreases stroke
volume more in diastolic dysfunction than in systolic
dysfunction.
I A S T O L I C D Y S F U N C T I O N — a condition in
which higher-than-normal left ventricular (LV) tilling pressures are needed to maintain a normal cardiac output—can cause
symptoms ranging from impaired exercise tolerance to overt left-sided or right-sided heart
failure. Although it causes fewer deaths than
systolic dysfunction, it is now thought to be
the underlying problem in at least one third of
all patients with congestive heart failure.
This article describes factors that contribute to diastolic dysfunction, different diagnostic techniques used to identify it, and goals
of pharmacotherapy.
•
SCOPE OF THE PROBLEM
Congestive heart failure is one of the most
prevalent medical conditions, with 5-year
mortality rates as high as 50% and health care
expenditures of close to $10 billion annually
in the United States alone. 1 The prevalence is
projected to rise as the population ages.2
Epidemiologic studies have shown that 30%
to 50% of patients with confirmed congestive
heart failure actually have adequate systolic
function, 3 so that diastolic dysfunction is now
believed to play an important role.
Furthermore, we now know that diastolic
dysfunction plays an important role in the
pathophysiology of the cardiomyopathies and
valvular, hypertensive, and ischemic heart disease.''
Effect on survival
Although the prognosis for patients with congestive heart failure due to diastolic dysfunction is better than for those with systolic dysfunction, recent studies indicate that the survival rate is lower in persons with diastolic
37 C L E V E L A N D C L I N I C J O U R N A L O F M E D I C I N E
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OCTOBER
2000
DIASTOLIC DYSFUNCTION
GARCIA
TABLE 1
At the cellular level, relaxation is energydependent and requires adenosine triphosphate for the reuptake of calcium by the sarcoplasmic reticulum, thus allowing the release
of the actin and myosin bridges. Since LV
relaxation is energy-dependent, ischemia
rapidly affects it.
Factors associated
with diastolic function
Afterload
Atrial function
Atrioventricular conduction
Heart rate
Intrathoracic pressure
Mitral valve function
Myocardial relaxation
Myocardial stiffness
Neurohormonal activation
Preload
Pericardial constraining effect
Right ventricular size and function
dysfunction than in those with normal diastolic function. 3
•
Symptoms can
range from
subtle exercise
intolerance to
overt
pulmonary
congestion
PATHOPHYSIOLOGY
Diastole starts when the aortic valve closes
and ends when the mitral valve closes and the
left ventricle starts to contract. At a normal
resting heart rate, diastole occupies about two
thirds of the entire cardiac cycle, but as the
heart rate increases, diastole shortens proportionally more than systole. This explains why
preventing tachycardia is an important therapeutic goal.
Several factors interact to determine diastolic function—ie, to maintain adequate cardiac output under normal filling pressure
(TABLE 1 ) 5 : the most important are LV relaxation and stiffness and left atrial function.
Patients with diastolic dysfunction can have
varying degrees of abnormality in these factors, resulting in symptoms ranging from subtle exercise intolerance to overt pulmonary
congestion and edema.
Left v e n t r i c u l a r r e l a x a t i o n
A normal ventricle relaxes forcefully, rapidly
decreasing its cavity pressure during early diastole and suctioning blood from the left atrium
across the mitral valve, 6 allowing the ventricle
to fill with blood in the presence of normal or
low left atrial pressure.
38
C L E V E L A N D C L I N I C J O U R N A L OF M E D I C I N E
VOLUME 67 • NUMBER 1 0
OCTOBER
Left ventricular diastolic stiffness
Once the LV pressure falls below the left atrial pressure, blood enters the left ventricle,
rapidly increasing its volume. This increasing
cavity volume causes the myocardial fibers to
stretch. The muscle fibers resist stretching in a
nonlinear fashion. Thus, the pressure required
to stretch a muscle fiber increases geometrically.7 The curvilinear relationship between filling pressure and volume is a measure of LV
diastolic stiffness. It is influenced by myocardial fiber distensibility, elasticity of the connective tissue, cavity diameter, wall thickness,
and the constraining effect of the pericardium.
In a normal left ventricle, stiffness is low during diastole, and relatively large increases in
volume cause relatively small increases in
pressure.
Left atrial f u n c t i o n
Left atrial function is an important determinant of LV diastolic function. The left atrium
acts as a reservoir of blood, as a conduit, and as
an active pump at the end of diastole.
According to the Frank-Starling mechanism,
the left atrial volume and pressure determine
the force of contraction. In younger, healthy
patients, the left atrial contribution is minimal
(< 20%); however, in patients with early diastolic dysfunction and impaired LV relaxation,
the left atrium compensates, increasing its
contractility and contributing up to 5 0 % of
the filling volume.
•
C O N D I T I O N S THAT CAUSE
DIASTOLIC DYSFUNCTION
A number of conditions are known to cause or
contribute to diastolic dysfunction (TABLE 2 ) .
Hypertensive
cardiomyopathy
and
ischemic heart disease are the most common
causes of diastolic dysfunction. Hypertensive
cardiomyopathy is responsible for about one
third of cases of heart failure requiring hospi2000
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talization. 8 Chronic arterial hypertension augments left ventricular systolic stress, inducing
hypertrophy of the myocardial sarcomeres in
parallel, thus increasing wall thickness. 9
Elevated angiotensin and insulin levels may
also contribute to the development of cardiac
hypertrophy.
Aging. The prevalence of diastolic dysfunction increases with age. The weight of the
heart increases between 1 g and 1.5 g per year
between the third and the ninth decade of
life, 10 and myocyte hypertrophy and an
increase in the connective tissue matrix, particularly in collagen type II, result in reduced
relaxation and increased stiffness. 11 Yet
despite these age-related abnormalities, most
older people do not have symptoms of heart
failure under normal circumstances. However,
they often develop symptoms of heart failure if
atrial fibrillation occurs.
Coronary artery disease affects left ventricular relaxation by limiting the availability
of energy substrates. Acute ischemia impairs
relaxation, and myocardial infarction increases stiffness due to interstitial fibrosis and scar
formation. 12
Restrictive cardiomyopathies. Diastolic
dysfunction is common in patients with
restrictive cardiomyopathies, disorders characterized by small left ventricular cavity size,
abnormal relaxation, and increased stiffness.15
Wall thickness is increased due to infiltration
or fibrosis and not to myocyte hypertrophy.
Therefore, the electrocardiographic Q R S
voltage is normal or low. Systolic function
may also be impaired in patients with
advanced disease. However, the ejection fraction is usually normal in patients with diastolic dysfunction.
Common causes of restrictive cardiomyopathy include primary and secondary amyloidosis, radiation treatment, glycogen storage
disorders, and some types of muscular dystrophy.
Hypertrophic cardiomyopathy causes
diastolic dysfunction via myocardial fiber disarray and a global or segmental increase in left
ventricular wall thickness. 14 LV chamber stiffness is increased and relaxation is impaired by
the asynchronous deactivation of muscle
fibers caused by abnormal electrical conduction. 15
TABLE
1
Cardiac conditions
associated with diastolic
dysfunction
Cardiac tamponade
Cardiomyopathies
Dilated
Hypertrophic
Restrictive
Chemotherapeutic drug toxicity
Congenital heart disease
Constrictive pericarditis
Hypertensive heart disease
Ischemic heart disease
Myocarditis
Transplant rejection
Constrictive pericarditis can cause diastolic dysfunction via increased LV stiffness
related to the constraining effects of a thickened and rigid pericardium. LV relaxation is
normal in these patients, and symptoms of
right heart failure predominate. 16 Subacute
cardiac tamponade usually presents with signs
and symptoms similar to those of constrictive
pericarditis.
Dilated cardiomyopathy. Alterations in
LV diastolic function are detected in most
patients with dilated cardiomyopathy. LV filling abnormalities have been shown to have
important independent prognostic implications in these patients. 17
•
First exclude
significant
pulmonary
parenchymal
or vascular
disease
DIAGNOSTIC TESTS HELPFUL
IN M E A S U R I N G DIASTOLIC DYSFUNCTION
The diagnosis of diastolic dysfunction in a
patient with dyspnea and exercise intolerance
requires careful analysis of the medical history, physical findings, and diagnostic test
results.
Exclude p u l m o n a r y disease, other causes
The first step should be to exclude significant
pulmonary parenchymal or vascular disease.
Chest radiography and spirometry with measurement of carbon monoxide diffusing capacity should be obtained according to the clini-
C L E V E L A N D C L I N I C J O U R N A L OF M E D I C I N E
V O L U M E 67 • NUMBER 1 0
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2 0 0 0 39
PLAVIX®
clopidogrel bisulfate tablets
B R I E F S U M M A R Y — Please see p a c k a g e insert for full prescribing information.
I N D I C A T I O N S A N D U S A G E : PLAVIX (clopidogrel bisulfate) is indicated for the reduction of atherosclerotic events (myocardial infarction, stroke, and vascular death) in patients with atherosclerosis
d o c u m e n t e d by recent stroke, recent myocardial infarction, or established peripheral arterial disease.
C O N T R A I N D I C A T I O N S : PLAVIX is contraindicated in patients with a hypersensitivity t o the drug
substance or any component of the product, and those with active pathologic bleeding such a s
peptic ulcer or intracranial hemorrhage.
W A R N I N G S : Thrombotic thrombocytopenic purpura (TTP): TTP has been reported rarely following use of
PLAVIX, sometimes after a short exposure (<2weeks). TTP is a serious condition requiring prompt treatment.
It is characterized by thrombocytopenia, microangiopathic hemolytic anemia (schistocytes [fragmented
RBCs] seen on peripheral smear), neurological findings, renal dysfunction, and fever. TTP was not seen during clopidogrel's clinical trials, which included over 11,300 clopidogrel-treated patients. In world-wide postmarketing experience, however, TTP has been reported at a rate of about four cases per million patients
exposed, or about 11 cases per million patient-years. The background rate is thought to be about four cases
per million person-years.
P R E C A U T I O N S : General: A s with other antiplatelet agents, PLAVIX should be used with caution
in patients w h o m a y b e at risk of increased bleeding from trauma, surgery, or other pathological
conditions. If a patient is to undergo elective surgery and an antiplatelet effect is not desired, PLAVIX
should be discontinued 7 days prior to surgery. G/ Bleeding: PLAVIX prolongs the bleeding time. In
CAPRIE, PLAVIX was associated with a rate of gastrointestinal bleeding of 2 . 0 % , vs. 2 . 7 % on
aspirin. PLAVIX should b e used with caution in patients w h o have lesions with a propensity to bleed
(such as ulcers). Drugs that might induce such lesions (such as aspirin and other nonsteroidal antiinflammatory drugs [NSAlDs]) should b e used with caution in patients taking PLAVIX. Use in
Hepatically Impaired Patients: Experience is limited in patients with severe hepatic disease, w h o
m a y have bleeding diatheses. PLAVIX should be used with caution in this population.
Information for Patients: Patients should b e told that it may take t h e m longer than usual to stop
bleeding when they t a k e PLAVIX, a n d that they should report any unusual bleeding to their physician. Patients should inform physicians and dentists that they are taking PLAVIX before any surgery
is scheduled and before any new drug is taken.
D r u g Interactions: Study of specific drug interactions yielded the following results: Aspirin: Aspirin
did not modify the cfopidogrel-mediated inhibition of A D P - i n d u c e d platelet aggregation.
Concomitant administration of 5 0 0 m g of aspirin twice a day for 1 day did not significantly increase
the prolongation of bleeding time induced by PLAVIX. PLAVIX potentiated the effect of aspirin o n
collagen-induced platelet aggregation. The safety of chronic concomitant administration of aspirin
and PLAVIX has not b e e n established. Heparin: In a study in healthy volunteers, PLAVIX did not
necessitate modification of the heparin dose or alter the effect of heparin on coagulation.
Coadministration of heparin h a d no effect on inhibition of platelet aggregation induced b y PLAVIX.
T h e safety of this combination has not been established, however, and concomitant use should be
undertaken with caution. Nonsteroidal Anti-Inflammatory
Drugs (NSAIDs): In healthy volunteers
receiving naproxen, concomitant administration of PLAVIX w a s associated with increased occult
gastrointestinal blood loss. NSAIDs and PLAVIX should be coadministered with caution. Warfarin:
T h e safety of t h e coadministration of PLAVIX (clopidogrel bisulfate) with warfarin has not been
established. Consequently, concomitant administration of these two agents should be undertaken
with caution. (See Precautions-General)- Other Concomitant
Therapy: No clinically significant
pharmacodynamic interactions were observed when PLAVIX w a s coadministered with atenolol,
nifedipine, or both atenolol and nifedipine. The pharmacodynamic activity of PLAVIX w a s also not
significantly influenced by the coadministration of phenobarbetal, cimetidlne or estrogen. T h e
pharmacokinetics of digoxin or theophylline were not modified by the coadministration of PLAVIX
(clopidogrel bisulfate). At high concentrations in vitro, clopidogrel inhibits P 4 c 0 (2C9). Accordingly,
PLAVIX may interfere with the metabolism of phenytoln, tamoxifen, tolbutamide, warfarin,
torsemide, fluvastatin, a n d many non-steroidal anti-inflammatory agents, but there are no d a t a
with which to predict t h e magnitude of these interactions. Caution should be used w h e n any of
these drugs is coadministered with PLAVIX. In addition to the above specific interaction studies,
patients entered into C A P R I E received a variety of concomitant medications including diuretics,
beta-blocking agents, angiotensin converting e n z y m e inhibitors, calcium antagonists, c h o lesterol lowering agents, coronary vasodilators, antidiabetic agents, antlepileptic a g e n t s and
hormone replacement therapy without evidence of clinically significant adverse interactions.
Drug/Laboratory Test Interactions: None known.
C a r c i n o g e n e s i s , Mutagenesis, Impairment of Fertility: There w a s no evidence of tumorigenicity
when clopidogrel w a s administered for 7 8 w e e k s to mice and 104 w e e k s to rats at dosages up to
7 7 m g / k g per day, which afforded plasma exposures > 2 5 times that in humans at the r e c o m m e n d ed daily dose of 7 5 mg. Clopidogrel was not genotoxic in four in vitro tests (Ames test, DNA-repair
test in rat hepatocytes, g e n e mutation assay in Chinese hamster fibroblasts, and m e t a p h a s e chrom o s o m e analysis of h u m a n lymphocytes) a n d in one in vivo test (micronucleus test by oral route in
mice). Clopidogrel was found to have no effect on fertility of male and female rats at oral doses up
to 4 0 0 mg/kg per day (52 times the recommended human dose on a m g / m 2 basis).
Pregnancy: Pregnancy Category B. Reproduction studies performed in rats and rabbits at doses
up to 5 0 0 and 3 0 0 m g / k g / d a y (respectively, 6 5 and 78 times the recommended daily h u m a n dose
on a m g / m 2 basis), revealed no evidence of impaired fertility or fetotoxicity due to clopidogrel. There
are, however, no a d e q u a t e and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of a human response, PLAVIX should be used during pregnancy only if clearly needed.
Nursing Mothers: Studies in rats have shown that clopidogrel and/or its metabolites are excreted
in the milk. It is not known whether this drug is excreted in h u m a n milk. Because many drugs are
excreted in human milk a n d because of the potential for serious adverse reactions in nursing infants,
a decision should b e m a d e whether to discontinue nursing or to discontinue the drug, taking into
account the importance of the drug to the nursing w o m a n .
Pediatric U s e : Safety a n d effectiveness in the pediatric population have not been established.
A D V E R S E R E A C T I O N S : PLAVIX (clopidogrel bisulfate) has been evaluated for safety in m o r e than
1 1 , 3 0 0 patients, including over 7 , 0 0 0 patients treated for 1 year or more. The overall tolerability of
PLAVIX was similar to that of aspirin regardless of age, gender and race, with an approximately
equal incidence ( 1 3 % ) of patients withdrawing from treatment because of adverse reactions. The
clinically important adverse events observed in C A P R I E are discussed below.
Hemorrhagic: In patients receiving PLAVIX in CAPRIE, gastrointestinal hemorrhage occurred at a
rate of 2 . 0 % , and required hospitalization in 0 . 7 % . In patients receiving aspirin, the corresponding
rates were 2 . 7 % a n d 1 . 1 % , respectively. The incidence of intracranial hemorrhage was 0 . 4 % for
PLAVIX compared to 0 . 5 % for aspirin. Neutropenia/agranulocytosis:
Ticlopidine, a drug chemically
similar to PLAVIX, is associated with a 0 . 8 % rate of severe neutropenia (less than 4 5 0 neutrophils/jxL). Patients in C A P R I E were intensively monitored for neutropenia. Severe neutropenia w a s
observed in six patients, four on PLAVIX a n d t w o on aspirin. Two of the 9 5 9 9 patients w h o received
PLAVIX and none of the 9 5 8 6 patients who received aspirin had neutrophil counts of zero. O n e of
the four PLAVIX patients was receiving cytotoxic chemotherapy, and another recovered and
returned to the trial after only temporarily interrupting treatment with PLAVIX. Although t h e risk of
myelotoxicity with PLAViX thus appears to b e quite low, this possibility should be considered when
a patient receiving PLAVIX demonstrates fever or other sign of infection. Gastrointestinal: Overall,
the incidence of gastrointestinal events (e.g., abdominal pain, dyspepsia, gastritis and constipation)
in patients receiving PLAVIX (clopidogrel bisulfate) w a s 27.1 % , compared to 2 9 . 8 % in those receiving aspirin. The incidence of peptic, gastric or duodenal ulcers w a s 0 . 7 % for PLAVIX and 1 . 2 % for
aspirin. Cases of diarrhea were reported in 4 . 5 % of patients in t h e PLAVIX group compared t o 3 . 4 %
in the aspirin group. However, these were rarely severe (PLAVIX = 0 . 2 % and aspirin = 0 . 1 % ) . The
incidence of patients withdrawing from treatment because of gastrointestinal adverse reactions w a s
3 . 2 % for PLAVIX and 4 . 0 % for aspirin. Rash and Other Skin Disorders: The incidence of skin and
a p p e n d a g e disorders in patients receiving PLAVIX w a s 1 5 . 8 % ( 0 . 7 % serious); the corresponding
rate in aspirin patients w a s 1 3 . 1 % ( 0 . 5 % serious). T h e overall incidence of patients withdrawing
from treatment b e c a u s e o f skin a n d a p p e n d a g e disorders adverse reactions w a s 1 . 5 % for PLAVIX
and 0 . 8 % for aspirin.
Body
System
Event
Adverse Events Occurring in > 2 . 5 % of P L A V I X Patients
% Incidence
( % Discontinuation)
PLAVIX
Aspirin
[11=9599]
[n=9586]
Body as a Whole - general disorders
Chest Pain
Accidental Injury
Influenza-like symptoms
Pain
Fatigue
8.3
7.9
7.5
6.4
3.3
Cardiovascular disorders, general
Edema
4.1
Hypertension
4.3
Central & peripheral nervous system disorders
Headache
7.6
Dizziness
6.2
Gastrointestinal system disorders
5.6
Abdominal pain
5.2
Dyspepsia
4.5
Diarrhea
3.4
Nausea
Metabolic & nutritional disorders
Hypercholesterolemia
4.0
Musculoskeletal
system disorders
Arthralgia
6.3
Back Pain
5.8
Platelet, bleeding, S clotting disorders
Purpura
5.3
Epistaxis
2.9
Psychiatric
disorders
Depression
3.6
Respiratory system disorders
Upper resp tract infection
8.7
Dyspnea
4.5
Rhinitis
4.2
Bronchitis
3.7
Coughing
3.1
Skin & appendage
disorders
Rash
4.2
Pruritus
3.3
Urinary system disorders
Urinary tract Infection
3.1
(0.2)
(0.1)
(<0.1)
(0.1)
(0.1)
8.3
7.3
7.0
6.3
3.4
(<0.1)
(<0.1)
4 . 5 (<0.1)
5.1 (<0.1)
(0.3)
(0.2)
7.2 (0.2)
6.7 (0.3)
(0.7)
(0.6)
(0.4)
(0.5)
7.1
6.1
3.4
3.8
(0)
4 . 4 (<0.1)
(0.1)
(0.1)
6 . 2 (0.1)
5 . 3 (<0.1)
(0.3)
(0.2)
3 . 7 (0.1)
2 . 5 (0.1)
(0.3)
(0.1)
(<0.1)
(0.1)
(0.1)
(1.0)
(0.7)
(0.3)
(0.4)
(0.1)
3 . 9 (0.2)
(<0.1)
(0.1)
(0.1)
(0.1)
(<0.1)
8.3
4.7
4.2
3.7
2.7
(0.5)
(0.3)
3 . 5 (0.2)
1.6 (0.1)
(0)
3 . 5 (0.1)
(<0.1)
(0.1)
(<0.1)
(0)
(<0.1)
Incidence of discontinuation, regardless of relationship to therapy, is shown in parentheses.
Adverse events occurring in > 2 . 5 % of patients on PLAVIX in the C A P R I E controlled clinical trial
are shown below regardless of relationship to PLAVIX. T h e median duration of therapy was 2 0
months, with a maximum of 3 years. Other adverse experiences of potential importance occurring
in 1 % to 2 . 5 % of patients receiving PLAVIX (clopidogrel bisulfate) in the C A P R I E controlled clinical
trial are listed below regardless of relationship to PLAVIX. In general, t h e incidence of these events
w a s similar in t h e aspirin-treated group. Autonomic Nervous System Disorders:
Syncope,
Palpitation. Body as a Whole - general disorders: Asthenia, Hernia. Cardiovascular disorders: Cardiac failure. Central and peripheral nervous system disorders: C r a m p s legs, Hypoaesthesia,
Neuralgia, Paresthesia, Vertigo. Gastrointestinal system disorders: Constipation, Vomiting. Heart
rate and rhythm disorders: Fibrillation atrial. Liver and biliary system disorders: Hepatic enzymes
increased. Metabolic and nutritional disorders: Gout, hyperuricemia, non-protein nitrogen (NPN)
increased. Musculoskeletal
system disorders: Arthritis, Arthrosis. Platelet, bleeding & clotting disorders: Gi hemorrhage, hematoma, platelets decreased. Psychiatric disorders: Anxiety, Insomnia.
Red blood cell disorders: Anemia. Respiratory system disorders: Pneumonia, Sinusitis. Skin and
a p p e n d a g e disorders: Eczema, Skin ulceration. Urinary system disorders: Cystitis. Vision disorders:
Cataract, Conjunctivitis. Other potentially serious adverse events which may b e of clinical interest
but were rarely reported (< 1 % ) in patients w h o received PLAVIX are listed below regardless of relationship to PLAVIX. In general, the incidence of these events w a s similar in the aspirin group. Body
as a whole: Allergic reaction, necrosis ischemic. Cardiovascular
disorders: E d e m a generalized.
Gastrointestinal system disorders: Gastric ulcer perforated, gastritis hemorrhagic, upper GI ulcer
hemorrhagic. Liver and Biliary system disorders: Bilirubinemia, hepatitis infectious, liver fatty.
Platelet, bleeding and clotting disorders: hemarthrosis, hematuria, hemoptysis, hemorrhage
intracranial, hemorrhage retroperitoneal, hemorrhage of operative wound, ocular hemorrhage, pulmonary hemorrhage, purpura allergic, thrombocytopenia. Red blood cell disorders: Anemia aplastic, anemia hypochromic. Reproductive disorders, female: Menorrhagia. Respiratory system disorders: Hemothorax. Skin and appendage disorders: Bullous eruption, rash erythematous, rash m a c ulopapular, urticaria. White cell and reticuloendothelial
system disorders: Agranulocytosis, granulocytopenia, leukemia, leukopenia, neutrophils decreased.
Postmarketing Experience: The following events have been reported spontaneously from worldwide
postmarketing experience; very rare cases of hypersensitivity reactions including angioedema, bronchospasms, and anaphylactoid reactions. Suspected thrombotic thrombocytopenic purpura (TTP) has been
reported as part of the world-wide postmarketing experience, see WARNINGS.
O V E R D O S A G E : O n e case of deliberate overdosage with PLAVIX (clopidogrel bisulfate) w a s reported in the large, controlled clinical study. A 34-year-old w o m a n took a single 1 , 0 5 0 - m g dose of
PLAVIX (equivalent to 14 standard 7 5 - m g tablets). There were no associated adverse events. No
special therapy was instituted, and she recovered without sequelae. No adverse events were reported after single oral administration of 6 0 0 m g (equivalent to 8 standard 7 5 - m g tablets) of PLAVIX in
healthy volunteers. T h e bleeding time w a s prolonged by a factor of 1.7, which is similar to that typically observed with the therapeutic dose of 7 5 m g of PLAVIX per day. A single oral dose of clopidogrel at 1 5 0 0 or 2 0 0 0 mg/kg w a s lethal to mice a n d to rats a n d at 3 0 0 0 m g / k g to baboons.
S y m p t o m s of acute toxicity were vomiting (in baboons), prostration, difficult breathing, and gastrointestinal hemorrhage in all species.
Recommendations About S p e c i f i c Treatment: Based on biological plausibility, platelet transfusion may b e appropriate to reverse the pharmacological effects of PLAVIX if quick reversal is
required.
D O S A G E A N D ADMINISTRATION: The r e c o m m e n d e d dose of PLAVIX is 75 m g once daily with or
without food.
Manufactured by:
Sanofi-Synthelabo Inc.
New York, NY 10016
Distributed by:
Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership
New York, NY 10016
SanOFi~Synf-helabO
H f l Bristol-Myers Squibb Company
PLAVIX® is a registered trademark of Sanofi-Synthelabo.
Revised April 2000
1081251A5
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1171DIM-07
cal history. Metabolic stress testing may help
to differentiate dyspnea from cardiac and pulmonary disease in different cases.
If there is a suspicion of chronic pulmonary embolism, a ventilation-perfusion
scan or high-resolution contrast computed
tomography should be obtained.
Significant anemia, thyrotoxicosis, mitral
and aortic valvular disease, and congenital
heart defects may all present with dyspnea and
heart failure and must be excluded. Coronary
artery disease may present with symptoms of
heart failure, the result of intermittent dysfunction induced by myocardial ischemia.
O u t m o d e d tests
Cardiac catheterization can establish the
diagnosis of heart failure, but it is rarely
required today for this purpose. It can estimate
LV relaxation from the rate of intracavitary
pressure decay during isovolumic relaxation—
ie, the interval between aortic valve closure
and mitral opening. LV stiffness is determined
by simultaneous assessment of LV volume and
LV pressure. Unfortunately, serial assessment
of these measurements is often necessary in
patients with suspected diastolic dysfunction,
and being an invasive procedure, cardiac
catheterization is not practical.
Radionuclide ventriculography can
assess the peak filling rate, the time to peak
filling rate, and the early-to-late filling ratio.
Radionuclide methods, however, have been
largely replaced by echocardiographic methods, which do not involve radiation exposure.
Echocardiographic t e c h n i q u e s
Echocardiography is the most important tool
for the diagnosis of diastolic heart dysfunction. 1 8 It is portable and safe. It excludes
other causes of heart failure (eg, valvular disease). Measurements obtained via different
echocardiographic techniques—ie,
twodimensional structural data and Doppler flow
velocities—may be combined to enhance the
evaluation.
Two-dimensional
echocardiography.
Significant diastolic dysfunction is unlikely in
the presence of a structurally normal heart.
Two-dimensional echocardiography evaluates
global and regional LV and right ventricular
FIGURE 1. Two-dimensional echocardiogram in a patient
with pure diastolic dysfunction. The left ventricle (LV)
demonstrates small cavity size and increased wall thickness.
The left atrium (LA) and right atrium (RA) are enlarged.
systolic function, mass, atrial size, and pericardial thickness (FIGURE 1 ) . It helps exclude
valvular heart disease and other causes of
heart failure. It also identifies left atrial
enlargement, caval and hepatic dilation, and
increased LV mass.
Doppler echocardiography measures
blood flow velocities across the mitral and tricuspid valves, in the pulmonary and hepatic
veins, and within the LV cavity.
With the onset of LV filling, the early atrioventricular pressure gradient accelerates the
blood across the mitral valve, generating the
early Doppler filling wave (the E wave). As
blood enters the left ventricle, LV pressure
increases and left atrial pressure decreases
until the gradient disappears or reverses, causing a deceleration of the early Doppler filling
wave. After a period of diastasis, the left atrium contracts, accelerating flow across the
mitral valve (the A wave).
We have found that a shorter deceleration
of the E wave may be associated with
increased LV stiffness.19 Furthermore, a short
733 C L E V E L A N D C L I N I C J O U R N A L OF M E D I C I N E
V O L U M E 6 7 • N U M BE R 1 0
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OCTOBER
2000
DIASTOLIC DYSFUNCTION
GARCIA
N o r m a l diastolic
function
M i l d diastolic
dysfunction
Pseudonormal
stage
Left ventricular relaxtion
Normal
4
u
vLNLNL
Left ventricular stiffness
Normal
Î
TÎ
ÎÎÎ
Left atrial contractility
Normal
Î
Normal
Preload
Normal
Normal
î
Electrocardiogram
JU
-A
E wave
í\rg
Mitral flow
Diastole
Pulmonary venous
flow
M
Restrictive-filling
stage
ÎÎ
i
J U - v
iL
dA -
_
Atrial reversal
v
Color M - m o d e v i e w
of f l o w p r o p a g a t i o n
in l e f t v e n t r i c l e
FIGURE 2. Doppler echocardiography shows how left ventricular (LV) relaxation, LV stiffness, and left
atrial contractility are altered in patients with mild diastolic dysfunction (ie, impaired relaxation) and
advanced diastolic dysfunction ("pseudonormal" stage and restrictive-filling stage). With the electrocardiogram as a reference, the mitral flow measurement shows, from left to right, first a decrease in
early filling (E) velocity due to decreased LV relaxation with a compensatory increase in atrial contraction (A) velocity, followed by an increase in E due to elevated filling pressures (pseudonormalization),
and finally, a short E deceleration time due to increased LV stiffness. Pulmonary venous flow velocity
measurements demonstrate changes in systolic and diastolic flow that also reflect the opposing effects
of alterations in LV relaxation and preload. The atrial reversal magnitude and duration increase with
increasing LV stiffness but may decrease when atrial systolic dysfunction occurs. Color M-mode shows
LV blood flow in both space and time. Decreasing LV relaxation increases the time that the column of
blood takes to reach the apex (Vp, white line).
E deceleration time in patients with restrictive 20 and dilated cardiomyopathy 21 has been
associated with reduced survival.
Doppler flow velocity measurement of the
left and right upper pulmonary veins provides
information about the systolic, diastolic, and
atrial reversal phases of pulmonary venous
734
C L E V E L A N D C L I N I C J O U R N A L OF M E D I C I N E
flow. This information can complement transmitral Doppler flow velocity measurements,
since the atrial reversal phase of pulmonary
venous flow appears to be strongly related to
left atrial contractility, 21 ' 22 and the magnitude
and duration of atrial reversal flow is directly
related to LV end-diastolic stiffness. 23
LUME 67 • NUMBER 1 0
OCTOBER
2000
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use only.
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TABLE 1
S t a g e s of diastolic d y s f u n c t i o n
NORMAL DIASTOLIC
FUNCTION
MILD DIASTOLIC
DYSFUNCTION
DELAYED
RELAXATION
Early-to-atrial
LV filling ratio
(cm/sec)
> 1
<
Early LV filling
deceleration time
(msec)
< 220
Isovolumic
relaxation time (ms)
ADVANCED DIASTOLIC
DYSFUNCTION
PSEUDONORMAL
FILLING
RESTRICTIVE
FILLING
1-2
>
>220
150-200
< 150
<100
> 100
60-100
< 60
Systolic-to-diastolic
pulmonary venous
flow ratio
>1*
> 1
<
<
Pulmonary venous
peak atrial contraction
reversed velocity
(cm/sec)
< 35
< 35
>35
>25
Flow propagation
velocity on color M - m o d e
echocardiography (cm/sec)
> 45+
< 45
< 45
<45
Peak early diastolic
myocardial velocity (cm/sec)
> 8*
1
1
2
1
'Less than 1 in young patients
•Greater than 55 cm/sec in young patients
•Greater than 10 cm/sec in young patients
ADAPTED FROM GARCIA ET AL. NEW DOPPLER ECHOCARDIOGRAPHIC APPLICATIONS FOR THE STUDY OF DIASTOLIC FUNCTION.
J AM COLL CARDIOL 1998; 32:865-875.
C o l o r M-mode Doppler echocardiography measures the spatiotemporal distribution of blood flow velocities within the
left ventricle. T h e velocity at which flow
propagates within the ventricle is indicated by the slope of the color wave-front (FIGURE 2). Because it contains both spatial and
temporal information, it quantitatively
estimates intraventricular pressure gradients, which are implicated in the generation of LV suction and relaxation. 6 Color
M-mode Doppler ventricular flow propagation is reduced in v e n t r i c l e s with
delayed r e l a x a t i o n ^ ( F I G U R E 2 ) . Combined
indices of color M-mode and pulsed
If chronic
pulmonary
embolism is
suspected,
obtain a V/Q
or CT scan
Doppler filling can be used to estimate LV
filling pressures in patients in the intensive care unit. 2 5
Tissue Doppler echocardiography displays the velocities of the myocardium during
contraction and relaxation. Clinical studies
show an inverse relationship between tissue
Doppler echocardiographic diastolic myocardial velocities and LV relaxation.^ These
velocities are useful in differentiating restrictive cardiomyopathy from constrictive pericarditis, 26 which are often difficult to distinguish in the clinical setting using two-dimensional and standard Doppler echocardiography
alone.
CLEVELAND CLINIC JOURNAL OF MEDICINE
V O L U M E 6 7 • NUMBER 1 0
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OCTOBER
2000
735
DIASTOLIC DYSFUNCTION
GARCIA
Diuretics reduce stroke volume more in diastolic than in systolic dysfunction
Systolic dysfunction
With
diuretics
O)
l/l
l/l
a>
Diastolic dysfunction
Without
diuretics
Without
diuretics
With
diuretics
Steeper slope
~ indicates increased
stiffness of
left ventricle
Q_
3
u
c
a>
>
End-diastolic
pressure
End-diastolic
pressure
Stroke volume
Stroke volume
Left ventricular v o l u m e
FIGURE 3. Pressure-volume
use of diuretics in patients
ular end-diastolic pressure,
d u e to t h e h i g h e r stiffness
Left ventricular v o l u m e
loops demonstrate the shift in the pressure-volume relationship w i t h the
w i t h systolic vs diastolic dysfunction. For the same reduction in left ventrict h e stroke v o l u m e decreases m o r e in t h e patient w i t h diastolic dysfunction
(steeper slope of d o t t e d line).
Echocardiographic o v e r v i e w
of diastolic dysfunction
Combining color M-mode and tissue Doppler
measurements with the Canadian Consensus
on Diastolic Dysfunction c r i t e r i a 4 , 2 7 provides
an overview of diastolic dysfunction (TABLE 3 ) :
• Normal diastolic function is characterized
by rapid LV relaxation, low stiffness, and normal filling pressures; the atrial contribution to
left ventricular filling is minimal
• Early diastolic dysfunction is characterized by a slow LV relaxation rate but relatively normal filling pressures; patients are asymptomatic or may have mild dyspnea during
exercise; and the atrial contribution to LV filling is increased, frequently more than 3 0 % of
the stroke volume
• Advanced diastolic dysfunction is characterized by an increase in LV filling pressure to
maintain cardiac output; the atrial contribution diminishes due to the elevated stiffness of
the left ventricle and atrial mechanical failure.
Advanced diastolic dysfunction can be
separated into a "pseudonormal" stage and a
2
736
C L E V E L A N D C L I N I C J O U R N A L OF M E D I C I N E
restrictive-filling stage, characterized by higher left ventricular stiffness and filling pressures. FIGURE 2 summarizes the alterations in LV
relaxation, LV stiffness, left atrial function,
and the diagnostic Doppler echocardiographic findings seen in patients with normal and
varying degrees of diastolic dysfunction.
•
TREATMENT OF DIASTOLIC
DYSFUNCTION
Treatment of diastolic dysfunction has the following goals:
• Resolve or control the underlying condition (eg, myocardial ischemia, hypertensive
heart disease, restrictive cardiomyopathy)
• Slow the heart rate to lengthen the duration of diastole
• Maintain atrial rhythm
• Avoid excessive use of diuretics.
To date, no large randomized trial has
been conducted to determine the effect of specific pharmacologic agents for the management of diastolic heart failure. However, evi-
O L U M E 67 • NUMBER 1 0
OCTOBER
2000
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All other uses require permission.
R e c o m m e n d e d dosage w i t h o r w i t h o u t food.
OA
y
200 mg qd
BRIEF S U M M A R Y C E L E B R E X ® (celecoxib capsules)
Before prescribing, please consult complete prescribing
information.
INDICATIONS AND U S A G E
For relief of the s i g n s and s y m p t o m s of O A , and of R A in adults.
CONTRAINDICATIONS
CELEBREX is contraindicated in patients with known hypersensitivity
to celecoxib. CELEBREX s h o u l d not be given to patients w h o have
d e m o n s t r a t e d allergic-type reactions to s u l f o n a m i d e s . CELEBREX
s h o u l d not be given to patients w h o have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other N S A I D s .
Severe, rarely fatal, anaphylactic-like reactions to N S A I D s have been
reported in s u c h patients (see W A R N I N G S — A n a p h y l a c t o i d Reactions, and P R E C A U T I O N S —Preexisting A s t h m a ) .
WARNINGS
Gastrointestinal (Gl) Effects —Risk of Gl Ulceration, Bleeding, and Perforation: S e r i o u s Gl toxicity s u c h as bleeding, ulceration, and perforation of the stomach, small intestine or large intestine, c a n occur at
any time, with or without w a r n i n g s y m p t o m s , in patients treated with
N S A I D s . Minor upper Gl problems, s u c h as d y s p e p s i a , are c o m m o n
and m a y also occur at any time during N S A I D therapy. Therefore,
p h y s i c i a n s a n d patients s h o u l d r e m a i n alert for ulceration a n d
bleeding, even in the absence of previous Gl tract s y m p t o m s . Patients
s h o u l d be informed about the s i g n s and/or s y m p t o m s of serious Gl
toxicity and the steps to take if they occur. Only 1/5 patients w h o
develop a serious upper Gl adverse event on N S A I D therapy is s y m p tomatic. Upper Gl ulcers, g r o s s bleeding or perforation, c a u s e d by
N S A I D s , appear to occur in approximately 1% of patients treated for
3 - 6 months, and in about 2 - 4 % of patients treated for one year. T h e s e
trends continue thus, increasing the likelihood of developing a serious
Gl event at s o m e time during the course of therapy. However, even
short-term therapy is not without risk. It is unclear, at the present time,
how the above rates apply to CELEBREX (see C L I N I C A L S T U D I E S —
S p e c i a l Studies in the complete prescribing information). A m o n g
5,285 patients w h o received CELEBREX in controlled clinical trials of
1 to 6 m o n t h s duration (most were 3 month studies) at a daily d o s e
of 200 mg or m o r e , 2 (0.04%) e x p e r i e n c e d s i g n i f i c a n t upper Gl
bleeding, at 14 a n d 22 d a y s after initiation of d o s i n g . Approximately
40% of these 5,285 patients were in studies that required them to be
free of ulcers by endoscopy at study entry. T h u s it is unclear if this
study population is representative of the general population. Prospective, long-term studies required to c o m p a r e the incidence of serious,
clinically s i g n i f i c a n t u p p e r G l a d v e r s e e v e n t s in patients taking
CELEBREX vs. comparator N S A I D products have not been performed.
N S A I D s s h o u l d be prescribed with extreme caution in patients with
a prior history of ulcer disease or Gl bleeding. Most s p o n t a n e o u s
reports of fatal Gl events are in elderly or debilitated patients and
therefore special care s h o u l d be taken in treating this population. To
m i n i m i z e the potential risk for an adverse Gl event, the lowest effective d o s e s h o u l d be used for the shortest possible duration. For high
risk patients, alternate therapies that do not involve N S A I D s s h o u l d
be considered. Studies have s h o w n that patients with a prior
history
of peptic ulcer disease and/or Gl bleeding and w h o use N S A I D s , have
a greater than 10-fold higher risk for developing a Gl bleed than
patients with neither of these risk factors. In addition to a past history
of ulcer disease, pharmacoepidemiological studies have identified
several other co-therapies or co-morbid conditions that m a y increase
the risk for Gl bleeding s u c h as: treatment with oral corticosteroids,
treatment with anticoagulants, longer duration of N S A I D therapy,
s m o k i n g , alcoholism, older age, a n d poor general health status.
A n a p h y l a c t o i d Reactions: A s with N S A I D s in general, anaphylactoid
reactions have occurred in patients without known prior e x p o s u r e to
CELEBREX. In post-marketing experience, rare c a s e s of anaphylactic
reactions and a n g i o e d e m a have been reported in patients receiving
CELEBREX. CELEBREX s h o u l d not be given to patients with the aspirin
triad. T h i s s y m p t o m c o m p l e x typically occurs in asthmatic patients
w h o experience rhinitis with or without nasal polyps, or w h o exhibit
severe, potentially fatal b r o n c h o s p a s m after taking aspirin or other
N S A I D s (see C O N T R A I N D I C A T I O N S and P R E C A U T I O N S - Preexisting
A s t h m a ) . E m e r g e n c y help s h o u l d be sought in c a s e s w h e r e an anaphylactoid reaction occurs.
A d v a n c e d R e n a l Disease: Treatment with CELEBREX is not recommended.
Pregnancy: In late pregnancy CELEBREX s h o u l d be avoided because
it m a y cause premature closure of the ductus arteriosus.
PRECAUTIONS
General: CELEBREX cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. T h e pharmacological
activity of CELEBREX in reducing inflammation, a n d p o s s i b l y fever,
m a y d i m i n i s h the utility of these diagnostic s i g n s in detecting infectious c o m p l i c a t i o n s of p r e s u m e d noninfectious, painful conditions.
Hepatic Effects: Borderline elevations of one or more liver tests may
occur in up to 15% of patients taking N S A I D s , and notable elevations
of A L T or A S T (approximately three or more times the upper limit of
normal) have been reported in approximately 1% of patients in clinical
trials with N S A I D s . T h e s e laboratory abnormalities m a y progress, may
remain u n c h a n g e d , or m a y be transient with continuing therapy.
Rare c a s e s of severe hepatic reactions, including jaundice and fatal
fulminant hepatitis, liver necrosis and hepatic failure (some with fatal
outcome) have been reported with N S A I D s , including CELEBREX. (See
A D V E R S E R E A C T I O N S —post-marketing experience.) In controlled
clinical trials of CELEBREX, the incidence of borderline elevations of
liver tests w a s 6 % for CELEBREX a n d 5% for placebo, a n d approximately 0.2% of patients taking CELEBREX and 0.3% of patients taking
p l a c e b o had notable elevations of A L T a n d A S T . A patient with
s y m p t o m s and/or s i g n s s u g g e s t i n g liver dysfunction, or in w h o m an
a b n o r m a l liver test has occurred, s h o u l d be monitored carefully for
evidence of the development of a more severe hepatic reaction w h i l e
on therapy with CELEBREX. If clinical s i g n s and s y m p t o m s consistent
with liver d i s e a s e develop, or if systemic manifestations occur (e.g.,
eosinophilia, rash, etc.), CELEBREX s h o u l d be discontinued.
Renal Effects: Long-term administration of N S A I D s has resulted in
renal papillary necrosis and other renal injury. Renal toxicity has also
been seen in patients in w h o m renal prostaglandins have a c o m p e n s a t o r y role in the m a i n t e n a n c e of renal p e r f u s i o n . In t h e s e
patients, administration of an N S A I D m a y cause a dose-dependent
reduction in prostaglandin formation and, secondarily, in renal blood
flow, w h i c h m a y precipitate overt renal decompensation. Patients at
greatest risk of this reaction are those with impaired renal function,
heart failure, or liver dysfunction, those taking diuretics and A C E inhibitors, a n d the elderly. Discontinuation of N S A I D therapy is usually
RA
J
^
lOOmg bid
followed b y recovery to the pretreatment state. Clinical trials with
CELEBREX have s h o w n renal effects similar to those observed with
comparator N S A I D s . Caution should be used w h e n initiating treatment with CELEBREX in patients with considerable dehydration. It is
a d v i s a b l e to rehydrate patients first and then start therapy with
CELEBREX. Caution is also r e c o m m e n d e d in patients with pre-existing
kidney disease (see W A R N I N G S — A d v a n c e d Renal D i s e a s e ) .
H e m a t o l o g i c a l Effects: A n e m i a m a y occur. In controlled clinical trials
the incidence of a n e m i a w a s 0.6% with CELEBREX and 0.4% with
placebo. Patients on long-term treatment with CELEBREX s h o u l d have
their h e m o g l o b i n or hematocrit checked if they exhibit any s i g n s or
s y m p t o m s of anemia or blood loss. CELEBREX d o e s not generally
affect platelet counts, prothrombin time (PT), or partial thromboplastin time (PTT), and does not appear to inhibit platelet a g g r e g a tion at Indicated dosages (See C L I N I C A L S T U D I E S - S p e c i a l S t u d i e s Platelets in the complete prescribing information).
Fluid Retention and Edema: Fluid retention and edema m a y occur (see
A D V E R S E R E A C T I O N S ) . Therefore, CELEBREX s h o u l d be used with
caution in patients with fluid retention, hypertension, or heart failure.
Preexisting A s t h m a : Do not use in patients with aspirin-sensitive
asthma because of the risk of severe bronchospasm. U s e with caution
in patients with preexisting asthma.
Laboratory Tests: Because serious Gl tract ulcerations a n d bleeding
can occur without w a r n i n g s y m p t o m s , physicians should monitor for
s i g n s or s y m p t o m s of Gl bleeding. During the controlled clinical
trials, there w a s an increased incidence of hyperchloremia in patients
receiving celecoxib c o m p a r e d with patients on placebo. Other laboratory abnormalities that occurred more frequently in the patients
receiving celecoxib included hypophosphatemia, and elevated B U N .
T h e s e laboratory a b n o r m a l i t i e s were also s e e n in patients w h o
received comparator N S A I D s in these studies. T h e clinical significance
of these abnormalities has not been established.
D r u g Interactions: General: Celecoxib metabolism is predominantly
mediated via cytochrome P450 2C9 in the liver. Co-administration of
celecoxib with d r u g s that are known to inhibit 2C9 s h o u l d be done
with caution. In vitro studies indicate that celecoxib, although not a
substrate, is an inhibitor of cytochrome P450 2D6. Therefore, there is
a potential for an in vivo drug interaction with d r u g s that are metabolized by P450 2D6. ACE-inhibitors:
Reports suggest that N S A I D s m a y
d i m i n i s h the a n t i h y p e r t e n s i v e effect of A n g i o t e n s i n C o n v e r t i n g
E n z y m e ( A C E ) inhibitors. T h i s interaction s h o u l d be given consideration in patients taking CELEBREX concomitantly with ACE-inhibitors.
Furosemide:
Clinical studies, as well as post marketing observations,
h a v e s h o w n that N S A I D s c a n r e d u c e the n a t r i u r e t i c effect of
furosemide and thiazides in s o m e patients. T h i s response has been
attributed to inhibition of renal p r o s t a g l a n d i n synthesis.
Aspirin:
CELEBREX can be used with low dose aspirin. However, concomitant
administration of aspirin with CELEBREX m a y result in an increased
rate of Gl ulceration or other complications, c o m p a r e d to use of
CELEBREX alone (see C L I N I C A L S T U D I E S - S p e c i a l S t u d i e s - G a s t r o intestinal in the complete prescribing information). Because of its lack
of platelet effects, CELEBREX is not a substitute for aspirin for cardiov a s c u l a r prophylaxis. Fluconazole:
Concomitant administration of
fluconazole at 200 m g QD resulted in a two-fold increase in celecoxib
p l a s m a concentration. T h i s increase is due to the inhibition of celec o x i b metabolism via P450 2C9 by fluconazole (see Pharmacokineti c s — M e t a b o l i s m ) . CELEBREX s h o u l d be introduced at the lowest reco m m e n d e d dose in patients receiving fluconazole. Lithium: In a study
c o n d u c t e d in healthy subjects, mean steady-state lithium plasma
levels increased approximately 17% in subjects receiving lithium 450
m g BID with CELEBREX 200 mg BID as c o m p a r e d to subjects receiving lithium alone. Patients on lithium treatment should be closely
monitored w h e n CELEBREX is introduced or withdrawn.
Methotrexate: In an interaction study of rheumatoid arthritis patients taking
methotrexate, CELEBREX did not have a significant effect on the pharmacokinetics of methotrexate. Warfarin: Anticoagulant activity should
be monitored, particularly in the first few d a y s , after initiating or
c h a n g i n g CELEBREX therapy in patients receiving warfarin or similar
agents, since these patients are at an increased risk of bleeding complications. T h e effect of celecoxib on the anticoagulant effect of
warfarin w a s studied in a g r o u p of healthy subjects receiving daily
d o s e s of 2 - 5 m g of warfarin. In these subjects, celecoxib did not alter
the anticoagulant effect of warfarin as determined by prothrombin
time. However, in post-marketing experience, bleeding events have
been reported, p r e d o m i n a n t l y in the elderly, in association with
increases in prothrombin time in patients receiving CELEBREX concurrently with warfarin. Carcinogenesis, m u t a g e n e s i s , i m p a i r m e n t of
fertility: Celecoxib w a s not carcinogenic in rats given oral d o s e s up
to 200 mg/kg for males and 10 mg/kg for females (approximately 2to 4-fold the h u m a n exposure as measured by the AUCo-24 at 200 mg
BID) or in mice given oral d o s e s up to 25 mg/kg for males and 50
mg/kg for f e m a l e s ( a p p r o x i m a t e l y equal to h u m a n e x p o s u r e as
m e a s u r e d b y the AUCo-24 at 200 m g BID) for two years. Celecoxib
w a s not mutagenic in an A m e s test and a mutation a s s a y in Chinese
hamster ovary (CHO) cells, nor clastogenic in a c h r o m o s o m e aberration a s s a y in C H O cells and an in vivo micronucleus test in rat bone
marrow. Celecoxib did not impair male and female fertility In rats at
oral d o s e s up to 600 mg/kg/day ( a p p r o x i m a t e l y 11-fold h u m a n
exposure at 200 m g BID based on the AUCo-24)P r e g n a n c y : Teratogenic
effects: Pregnancy C a t e g o r y C. Celecoxib
w a s not teratogenic in rabbits up to an oral d o s e of 60 mg/kg/day
(equal to h u m a n exposure at 200 m g BID as m e a s u r e d by AUCo-24);
however, at oral d o s e s > 1 5 0 mg/kg/day (approximately 2-fold h u m a n
exposure at 200 mg BID as m e a s u r e d by ÁÜC0-24), an increased incidence of fetal alterations, s u c h as ribs fused, sternebrae fused and
sternebrae m i s s h a p e n , w a s observed. A dose-dependent increase in
diaphragmatic hernias was observed in one of two rat studies at oral
d o s e s 3:30 mg/kg/day (approximately 6-fold h u m a n e x p o s u r e based
on the AUCo-24 at 200 mg BID). There are no studies in pregnant
w o m e n . CELEBREX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nonteratogenic
effects: Celecoxib produced preimplantation and post-implantation
losses a n d reduced embryo/fetal survival in rats at oral d o s a g e s > 5 0
mg/kg/day (approximately 6-fold h u m a n e x p o s u r e b a s e d on the
AUCO-24 at 200 mg BID). T h e s e c h a n g e s are expected with inhibition
of prostaglandin synthesis and are not the result of permanent alteration of female reproductive function, nor are they expected at clinical
exposures. No studies have been conducted to evaluate the effect of
celecoxib on the closure of the ductus arteriosus in h u m a n s . Therefore, use of CELEBREX during the third trimester of p r e g n a n c y s h o u l d
be avoided. L a b o r a n d delivery: Celecoxib produced no evidence of
delayed labor or parturition at oral d o s e s up to 100 mg/kg in rats
(approximately 7-fold h u m a n exposure as m e a s u r e d by the AUCO-24
at 200 m g BID). T h e effects of CELEBREX on labor a n d delivery in
pregnant w o m e n are unknown. N u r s i n g mothers: It is not known
whether this drug is excreted in h u m a n milk. B e c a u s e m a n y drugs
J>
TO
200 mg bid
are excreted in h u m a n milk and b e c a u s e of the potential for serious
adverse reactions in nursing infants from CELEBREX, a decision should
be m a d e whether to discontinue nursing or to discontinue the drug,
taking into account the importance of the drug to the mother.
Pediatric Use: Safety and effectiveness in pediatric patients below the
age of 18 years have not been evaluated.
Geriatric Use: Of the total number of patients w h o received CELEBREX
in clinical trials, more than 2,100 were 6 5 - 7 4 years of age, while
approximately 800 additional patients w e r e 75 years and over. While
the incidence of adverse experiences tended to be higher in elderly
patients, no substantial differences in safety and effectiveness were
observed between these subjects and y o u n g e r subjects. Other
reported clinical experience has not identified differences in response
between the elderly and y o u n g e r patients, but greater sensitivity of
s o m e older individuals cannot be ruled out. In clinical studies c o m paring renal function as m e a s u r e d by the G F R , B U N and creatinine,
and platelet function as m e a s u r e d by bleeding time and platelet
aggregation, the results were not different between elderly and y o u n g
volunteers.
ADVERSE REACTIONS
Adverse events occurring in 5 2 % of Celebrex patients from controlled
a r t h r i t i s t r i a l s , r e g a r d l e s s of c a u s a l i t y at r e c o m m e n d e d d o s e s
(N=4146): a b d o m i n a l pain 4.1%, diarrhea 5.6%, d y s p e p s i a 8.8%, flatulence 2.2%, nausea 3.5%, back pain 2.8%, peripheral edema 2.1%,
injury-accidental 2.9%, dizziness 2.0%, headache 15.8%, i n s o m n i a
2.3%, pharyngitis 2.3%, rhinitis 2.0%, sinusitis 5.0%, upper respiratory
tract infection 8.1%, rash 2.2%. In placebo- or active-controlled clinical
trials, the discontinuation rate d u e to a d v e r s e events w a s 7.1% for
patients receiving CELEBREX and 6 . 1 % for patients receiving placebo.
A m o n g the most c o m m o n reasons for discontinuation due to adverse
events in the CELEBREX treatment g r o u p s w e r e dyspepsia and abdominal pain (cited as reasons for discontinuation in 0.8% and 0.7% of
CELEBREX patients, respectively). A m o n g patients receiving placebo,
0.6% discontinued due to d y s p e p s i a a n d 0 . 6 % w i t h d r e w due to
abdominal pain. The following adverse events occurred in 0 . 1 - 1 . 9 %
of patients regardless of causality.
Celebrex (100-200 m g BID or 200 m g QD): Gl: Constipation, diverticulitis, d y s p h a g i a , eructation, esophagitis, gastritis, gastroenteritis,
g a s t r o e s o p h a g e a l reflux, h e m o r r h o i d s , hiatal hernia, melena, dry
mouth, stomatitis, tenesmus, tooth disorder, vomiting;
Cardiovascular:
A g g r a v a t e d hypertension, a n g i n a pectoris, coronary artery disorder,
myocardial infarction; General: A l l e r g y aggravated, allergic reaction,
asthenia, chest pain, cyst N O S , e d e m a generalized, face edema,
fatigue, fever, hot flushes, influenza-like s y m p t o m s , pain, peripheral
pain; Resistance
mechanism
disorders:
Herpes simplex, herpes
zoster, infection bacterial, infection fungal, infection soft tissue, infection viral, moniliasis, moniliasis genital, otitis media; Central,
peripheral nervous
system:
Leg cramps, hypertonia, hypoesthssia,
migraine, neuralgia, neuropathy, paresthesia, vertigo; Female
reproductive: Breast fibroadenosis, breast n e o p l a s m , breast pain, dysmenorrhea, menstrual disorder, v a g i n a l h e m o r r h a g e , vaginitis; Male
reproductive:
Prostatic disorder; Hearing and vestibular:
Deafness,
ear abnormality, earache, tinnitus; Heart rate and rhythm: Palpitation,
tachycardia; Liver and biliary system: Hepatic function abnormal,
S G O T increased, S G P T increased; Metabolic and nutritional:
BUN
increased, C P K increased, diabetes mellitus, hypercholesterolemia,
hyperglycemia, hypokalemia, N P N increase, creatinine increased,
alkaline phosphatase increased, weight increase;
Musculoskeletal:
Arthralgia, arthrosis, bone disorder, fracture accidental, myalgia, neck
stiffness, synovitis, tendinitis; Platelets (bleeding or clotting):
Ecchymosis, epistaxis, thrombocythemia; Psychiatric:
Anorexia, anxiety,
appetite increased, depression, n e r v o u s n e s s , s o m n o l e n c e ; Hemic:
A n e m i a ; Respiratory:
Bronchitis, b r o n c h o s p a s m , b r o n c h o s p a s m agg r a v a t e d , c o u g h i n g , d y s p n e a , l a r y n g i t i s , p n e u m o n i a ; Skin
and
appendages:
A l o p e c i a , dermatitis, nail disorder, photosensitivity
reaction, pruritus, rash e r y t h e m a t o u s , r a s h m a c u l o p a p u l a r , s k i n
disorder, skin dry, s w e a t i n g increased, urticaria; Application
site
disorders:
Cellulitis, dermatitis contact, injection site reaction, skin
nodule; Special senses: Taste perversion; Urinary system:
Albuminuria, cystitis, dysuria, hematuria, micturition frequency, renal calculus,
urinary incontinence, urinary tract infection; Vision: Blurred vision,
cataract, conjunctivitis, eye pain, g l a u c o m a .
O t h e r s e r i o u s a d v e r s e r e a c t i o n s w h i c h o c c u r rarely ( e s t i m a t e d
< 0 . 1 % ) , r e g a r d l e s s of c a u s a l i t y : T h e f o l l o w i n g s e r i o u s a d v e r s e
e v e n t s h a v e o c c u r r e d rarely in patients taking CELEBREX. C a s e s
reported only in the post-marketing experience are indicated in italics.
Cardiovascular:
S y n c o p e , congestive heart failure, ventricular fibrillation, p u l m o n a r y e m b o l i s m , c e r e b r o v a s c u l a r accident, peripheral
g a n g r e n e , thrombophlebitis, vasculitis;
Gl: Intestinal obstruction,
intestinal perforation, gastrointestinal bleeding, colitis with bleeding,
esophageal perforation, pancreatitis, ileus; Liver and biliary
system:
Cholelithiasis, hepatitis, jaundice, liver failure; Hemic and
lymphatic:
Thrombocytopenia, agranulocytosis,
aplastic anemia,
pancytopenia,
leukopenia;
Metabolic:
Hypoglycemia;
Nervous
system:
Ataxia,
suicide; Renal: Acute renal failure, interstitial nephritis; Skin:
Erythema
multiforme, exfoliative dermatitis, Stevens-Johnson
syndrome,
toxic
epidermal necrolysis; General: S e p s i s , s u d d e n death,
anaphylactoid
reaction,
angioedema.
OVERDOSAGE
S y m p t o m s following acute N S A I D o v e r d o s e s are usually limited to
lethargy, drowsiness, nausea, vomiting, a n d epigastric pain, which are
generally reversible with supportive care. Gl bleeding can occur.
Hypertension, acute renal failure, respiratory depression and c o m a
m a y occur, but are rare. A n a p h y l a c t o i d reactions have been reported
with therapeutic ingestion of N S A I D s , a n d m a y occur following an
overdose. Patients should be m a n a g e d by s y m p t o m a t i c a n d supportive care following an N S A I D overdose. T h e r e are no specific antidotes. No information is available regarding the removal of celecoxib
by hemodialysis, but based on its h i g h degree of plasma protein
binding ( > 9 7 % ) dialysis is unlikely to be useful in overdose. E m e s i s
and/or activated charcoal (60 to 100 g in adults, 1 to 2 g/kg in children)
and/or osmotic cathartic m a y be indicated in patients seen within 4
hours of ingestion with s y m p t o m s or f o l l o w i n g a large overdose.
Forced diuresis, alkalinization of urine, h e m o d i a l y s i s , or hemoperfusion may not be useful due to high protein binding.
Mfd. by Searle Ltd.
Caguas PR 00725
Marketed by: G.D. Searle & Co.
Chicago IL 60680 USA
Pfizer Inc., New York NY 10017 USA
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dence supports that most treatments for systolic heart failure also improve diastolic dysfunction.
•
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Afterload reduction
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Verapamil has been reported to improve
LV relaxation and symptoms in some familial
forms of hypertrophic cardiomyopathy. 28
However, calcium channel blockers can cause
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A C E inhibitors have been shown to
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Most agents
for systolic
heart failure
also improve
diastolic
dysfunction
OCTOBER
46 September
C L E V E L A N D 9,C L2014.
I N I C JFor
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C I N E All other
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2000
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Dear Doctor:
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Cleveland Clinic Journal
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20.
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G a r c i a M J , R o d r i g u e z L, A r e s M A , G r i f f i n BP, T h o m a s
JD, K l e i n AL. D i f f e r e n t i a t i o n o f c o n s t r i c t i v e p e r i c a r d i t i s
f r o m restrictive c a r d i o m y o p a t h y : Assessment o f left
v e n t r i c u l a r d i a s t o l i c v e l o c i t i e s in t h e l o n g i t u d i n a l axis
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H e a r t J 1 9 9 9 ; 1 3 8 ( 4 Pt 1 ) : 7 1 0 - 7 2 0 .
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CLEVELAND CLINIC JOURNAL OF MEDICINE
The Cleveland Clinic Foundation
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R o s s v o l l O , H a t l e LK. P u l m o n a r y v e n o u s f l o w v e l o c i t i e s
r e c o r d e d by t r a n s t h o r a c i c D o p p l e r u l t r a s o u n d : r e l a t i o n
t o l e f t v e n t r i c u l a r d i a s t o l i c pressures. J A m C o l l C a r d i o l
1993; 2 1 : 1 6 8 7 - 1 6 9 6 .
G a r c i a M J , T h o m a s JD, Klein AL. N e w D o p p l e r
echocardiographic applications for t h e study of
diastolic f u n c t i o n . J A m Coll C a r d i o l 1998;
32:865-875.
ADDRESS:
Mario J. Garcia, MD, Department
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Cardiology,
Avenue,