Volume 2, Number 1: January 1999
Noninvasive Detection of AtherosclerosisTablets That Can Be Halved to Save CostsViagra unsafe for some heart patientsCan Hard Work Damage Your Health? Noninvasive Detection of Atherosclerosis
Reference: NEJM 1998;339(27):2014.
Atherosclerosis has been a serious health epidemic in developed
countries in the late 20th century, and its rising prevalence in
developing nations suggests that it will become the chief cause
of morbidity and mortality worldwide by early in the next
century. Although the principal clinical complications of
atherosclerosis, such as myocardial infarction and stroke,
usually occur in middle-aged or older people, the atherogenic
process actually begins in childhood and early adult life, with a
preclinical phase lasting many decades. This pattern provides a
window of opportunity for the presymptomatic detection of the
disease, the identification of high-risk subjects, and the
application of appropriate preventive strategies.
Recent advances have defined many of the early molecular and
cellular changes that occur during atherogenesis. Some of these
processes provide a focus for diagnostic assays. Oxidative
modification of lipoproteins, adhesion of monocytes to vascular
endothelium, foam-cell formation, and arterial-wall thickening
occur during childhood or young adult life in persons at high
risk. Dysfunction of the arterial endothelium is also an
important early event, with decreased local availability of
nitric oxide and thus impaired vasodilator capacity. Inflammation
and calcification of plaques may be slightly later events, but
they still usually precede luminal narrowing and the onset of
symptoms.
Ideally, clinical testing for atherosclerosis should involve
methods that are safe, inexpensive, noninvasive or minimally
invasive, reliable, and reproducible; their results should
correlate with the extent of atherosclerotic disease and have
high positive and negative predictive values for clinical events.
Although no such techniques are yet available, the areas
currently of greatest interest include blood tests for
atherosclerosis, vascular ultrasonography, magnetic resonance
imaging (MRI), and electron-beam computed tomography (CT).
So far, blood tests for atherosclerosis have emphasized the
measurement of predisposing risk factors, such as high levels of
cholesterol, lipoprotein subfractions, and homocysteine. Newer
tests may detect markers released from areas of early atheroma --
for example, novel lipid or protein oxidation products or
adhesion molecules specific for atherosclerosis. The levels of
less specific markers of endothelial activation or inflammation,
such as C-reactive protein and intercellular adhesion molecule 1,
have recently been shown in population studies to correlate
significantly with the risk of future vascular
complications, but assays for these markers cannot yet be
recommended for use in individual patients.
Noninvasive ultrasonography has also been used to detect early
signs of atherogenesis, such as impaired endothelial function and
arterial-wall thickening in peripheral arteries. These tests are
safe and quick; their results are reproducible and correlate with
major cardiovascular risk factors, as well as with the extent of
coronary atherosclerosis. Recent studies have also demonstrated
that greater carotid intima-media thickness predicts a greater
likelihood of subsequent cardiovascular events in high-risk
persons, a finding that suggests that ultrasonography will have
increasing value in the presymptomatic detection of early
atherosclerosis.
MRI is already in clinical use for the detection of peripheral
and cerebral atherosclerosis. MRI of the coronary circulation has
proved more challenging because of cardiac and respiratory
motion. MRI has also recently been used to obtain images of
plaque in the vessel wall, both in animals and in superficial
human arteries, allowing measurements of plaque size as well as
visualization of the fine structure of lesions, such as the
fibrous cap and necrotic core. Although costly, MRI therefore
holds promise for future studies of plaque and its effects on the
diameter of the lumen.
Electron-beam (or "ultrafast") CT is an exciting
technique in coronary imaging. It differs from conventional CT in
that the x-ray source does not need to be rotated around the
patient, allowing much faster acquisition. Because
calcification is an early feature of atherosclerotic-plaque
formation, measurement of coronary calcium by means of CT
scanning of the heart may reflect the extent of atherosclerosis.
In general, calcium makes up approximately 20 percent of
atherosclerotic-plaque volume and is significantly correlated
with the total burden of plaque. Deposition of calcium
hydroxyapatite in plaque is an active process, and
atherosclerotic areas may express genes related to calcium
metabolism, such as those for osteopontin and
osteocalcin.Nevertheless, some high-grade lesions and many
smaller plaques lack calcium altogether. High coronary
calcium scores have good sensitivity for obstructive coronary
disease (80 to 100 percent), but low specificity (40 to 60
percent). Some studies, but not all, that have prospectively
examined the value of indexes of coronary calcium for predicting
clinical events have documented low rates of complications among
those with no coronary calcium and a relatively high risk among
asymptomatic subjects with high calcium scores.
In this issue of the Journal, Callister et al. describe the use
of a new, reproducible calcium-volume score in assessing the
coronary circulation in a cohort of asymptomatic subjects. In a
retrospective review, the authors found less progression of the
calcium-volume score in patients who were treated with
lipid-lowering agents than in untreated subjects (particularly if
treatment resulted in a level of low-density lipoprotein
cholesterol that was below 120 mg per deciliter [3.1 mmol per
liter]). Although this suggests slower progression of plaque
growth with effective lipid lowering, it is uncertain whether a
change in the calcium-volume score represents a change in plaque
size, in the composition of the lesion, in the degree of
vulnerability to rupture, or a combination of these factors.
Several other mechanisms that may explain the apparent benefit of
lipid-lowering therapy in terms of arterial structure and
vasomotion have recently been documented, including improved
endothelial function with less coronary constriction and
increased stability of plaques. Reduction in coronary calcium,
therefore, may also contribute to the observed clinical benefit
of lipid-lowering treatment in high-risk subjects with
hypercholesterolemia.
Elsewhere in this issue of the Journal, Achenbach and colleagues
report the results of their examination of the role of
contrast-enhanced electron-beam CT for the assessment of coronary
luminal size in symptomatic patients who were undergoing
conventional coronary angiography. In approximately 65 percent of
patients, technically adequate CT images of all the major
coronary arteries were obtained. In these cases, the authors
could accurately classify subjects according to whether they did
or did not have high-grade coronary stenoses (>75 percent) or
occlusions. Furthermore, the negative predictive value of the
technique in patients without severe stenoses on CT was 98
percent. With the caveat that relatively minor plaques are often
the culprit lesions in acute coronary syndromes,
contrast-enhanced CT may permit certain patients with chest pain
to be evaluated and treated without cardiac catheterization.
Conventional coronary angiography, however, remains relatively
quick, entails a low risk, generally clarifies the severity of
obstructive stenoses in all the major proximal and distal
epicardial vessels, and allows immediate catheter-based
intervention, if indicated. Further studies are now required to
evaluate the clinical implications of this exciting new research
for the diagnostic workup of patients with suspected coronary
disease.
Coronary imaging with electron-beam CT is therefore a promising
noninvasive method that may contribute to overall risk
assessment. Calcium-volume scoring may provide information on the
extent of atherosclerosis in the coronary arteries, and
contrast-enhanced CT may determine the severity of the disease.
Before the routine clinical use of coronary CT scanning can be
recommended for screening of asymptomatic patients or for the
evaluation of patients with chest pain, however, more work is
needed. Basic studies are required to define the role of calcium
in plaque stability and progression, and prospective studies are
needed to demonstrate the cost effectiveness of these techniques
and their potential impact on cardiovascular outcomes. As the
prevalence of atherosclerosis increases worldwide, there is a
pressing need for investigators to refine and evaluate these and
other noninvasive techniques, in order to ensure reliable
detection of atherosclerosis during the long presymptomatic phase
of the disease.
Tablets
That Can Be Halved to Save Costs
Reference: Drug
Benefit Trends 1998;10(12):31.
Some tablets available by prescription can easily be split in
half in order to save the patient money while still providing the
optimal dose for his or her medical condition. Tablets that are
scored and large enough to allow a firm grip on each end are
probably the most conducive to splitting. It is important to
consider drugs that have a wide therapeutic window, where the
risk for drug toxicity or therapeutic failure is insignificant.
For pediatric patients and the elderly, it may be necessary to
use half-tablets to provide smaller dosages of a medication than
those supplied by the manufacturer. Many oral tablet prescription
preparations can be divided without extensively altering their
pharmacologic properties, yielding significant cost savings to
the patient.
In some situations, tablets are not intended by their
manufacturers to be broken in half because of their size,
thickness, or design. And many states do not allow the dispensing
of split tablets.
However, with medications that are conducive to splitting, the
patient can buy an inexpensive "tablet splitter"
(usually less than $10), a rigid plastic box with a partition in
which a tablet can be placed for splitting. A steel blade affixed
to the lid cuts the tablet when the device is closed. While a
tablet splitter may be a good alternative for some patients, 1
study found that tablet splitters did not improve the accuracy of
dividing tablets into 2 equal parts. If a tablet splitter is
going to be used, patients should be instructed about the proper
placement of the tablet to avoid cutting themselves when placing
or removing a tablet. If a tablet shatters when split or does not
consistently break in half when division is attempted, it is
surely not a candidate for splitting.
The health care provider and patient may be concerned about the
accuracy of tablet splitting and the exact amount of
pharmacologically active drug that is obtained; there can be
variability in the ideal tablet weight once it is split in
half.[2,3] Drugs that have a wide therapeutic window, where the
risk for toxicity or therapeutic failure is insignificant, are
good options for tablet splitting.
For the most part, tablets that are elongated and deeply scored
on both sides are easily split in half. They should also be large
enough to permit a firm grip on each end. A patient or provider
should avoid splitting, crushing, or manipulating
extended-release tablets, such as glipizide (Glucotrol XL), as
well as those that contain a wax or matrix coating.
In this researcher's clinical experience, these examples have led
to cost savings, easy tablet splitting, and patient satisfaction.
For example, many patients can be treated effectively for
depression with sertraline (Zoloft) at half the recommended
dosage (50mg once daily). Another drug that can be easily split
is mirtazapine (Remeron); a half tablet (15mg) in the evening can
control depression in many individuals.
Valacyclovir (Valtrex) 1g tablets, used for the suppression of
genital herpes, can easily be split in half to accommodate the
recommended daily dose of 500mg. Fluvoxamine (Luvox), used to
treat obsessive-compulsive disorder, can be initiated at a dosage
of 50mg (half a tablet) daily. However, unless they have liver
dysfunction or are sensitive to higher doses because they are
elderly, most patients will need a higher dose for maintenance
therapy.
At average wholesale price, use of the drugs can lead to a cost
decrease of about 50%. For example, if a prescription is written
for sertraline 50mg daily, the patient could use number 15 of the
100mg tablets at an average wholesale cost of $34.17.[4] For many
patients this cost saving is significant.
Given the ongoing search for drug cost-effectiveness, tablet
splitting, in appropriate situations, should be considered. The
splitting of certain medications can lead to substantial cost
savings.
Viagra
unsafe for some heart patients
Reference: Journal
of the American College of Cardiology 1999;33:273-282.
Viagra, the new impotence drug, is not safe for heart patients
who take organic nitrates, such as nitroglycerin patches or
nitroglycerin tablets placed under the tongue, according to
physician prescribing guidelines issued jointly by the American
College of Cardiology and the American Heart Association.
Certain other heart patients should have a thorough check-up
before a doctor prescribes Viagra, according to the document,
which is published in the January issue of the Journal of the
American College of Cardiology and the January 5th issue of
Circulation: Journal of the American Heart Association.
A consensus committee -- a group of experts who review the
available scientific research and formulate recommendations for
other physicians, developed the guidelines.Although definitive
evidence is currently lacking, it is possible that a precipitous
reduction in blood pressure with nitrate use may occur over the
initial 24 hours after a dose of Viagra,'' the authors write.
Sudden drops in blood pressure can be life threatening, they
note.
The committee recommends a thorough medical examination for any
man who wants to try Viagra but meets any of the
following criteria:
-- Has chest pain or another sign of poor blood flow to the
heart.
-- Has congestive heart failure and low blood pressure.
-- Is taking several drugs to control high blood pressure.
-- Has kidney or liver disease or takes a medication that affects
how long Viagra stays in the body.
In a statement released by the American College of Cardiology,
Dr. Melvin D. Cheitlin of the University of California, San
Francisco, a co-chair of the committee's writing group, said that
the committee's goal was ``to appropriately caution, and not to
unduly alarm, physicians who may wish to prescribe the drug to
their patients with cardiovascular disease.''
US Food and Drug Administration has confirmed reports of 69
deaths associated with Viagra use. The cause of death is known
for 48 deaths, including 2 from strokes and 46 from heart
attacks.
Can
Hard Work Damage Your Health?
Reference: BMJ 1998; 317: 775-80
Summary: It is a commonly held belief that a stressful job with
long working hours may predispose to an increased risk of
myocardial infarction. There have been few studies to test this
hypothesis. Randomized trials would be almost impossible. This is
a report of a case-control study from Japan that investigates
whether long working hours or a change in working hours
influences the risk of acute myocardial infarction (AMI).The
cases were 195 male patients admitted to four hospitals over a
3-year period with a diagnosis of first AMI. The diagnosis was
based on the history combined with typical EKG changes and
rise in cardiac enzymes. The 331 male control subjects were
selected at annual routine workplace medical exams from men
believed to be free of cardiovascular disease. These medical
exams included measurements of serum lipids and
electrocardiography in addition to standard clinical examination.
Controls were matched to cases for occupational categories
(as defined by the Japanese census).
All participants completed a questionnaire concerning working
hours. Mean working hours per day were recorded for the 2
months before the AMI and also for the 2 months with the longest
and shortest working hours in the previous year. Recall was
aided by the detailed work time sheets available to Japanese
workers. This information was used to derive changes in working
hours. A validated questionnaire was used as a "burnout
measure" - it asked 21 questions about positive and negative
feelings in
the month before the AMI. For control subjects, the reference
date was the date of recruitment into the study.
It was concluded that there was a U shaped relation between the
mean monthly working hours of our subjects and their risk of
acute myocardial infarction. In addition, there seemed to be a
trend for the risk of acute myocardial infarction to increase
with greater increases in working hours. Further study is
necessary to clarify the mechanism for the U shaped association
and its influence on the low morbidity and mortality from acute
myocardial infarction in Japan.