MEDICAL SUBJECT
HEADINGS
HIGHLIGHTS-INDEX
STATEMENT BY THE EDITOR/PUBLISHER
This Highlights-Index
begins with 162 medical subject headings (MESH). These act as a directory to
the following 65 pages of highlights of articles abstracted from 6 flagship
journals during 2003.
The
highlights are designed for 2 purposes:
1.
In one or two evenings, clinicians can rapidly scan, read, review, and recall
to memory the studies and commentaries the editor considered to be new,
clinically important, and interesting.
Some highlights also contain the editor’s comments on the clinical
applicability of the article based on his years-long experience as a primary
care internist.
2.
The highlights can be used repeatedly for years as a reference.
I
format the highlights so that the reader can easily refer to the full abstracts
in each monthly issue of Practical
Pointers. They are labeled
according to the month and year (eg, 10-4 is the 4th article
abstracted in October). The monthly
issues can be accessed on the internet at www.practicalpointers.org in both
HTML and pdf formatting.
The
links in the HTML yearly index progress from the MESH to the highlights, and to
the more detailed abstract. Each abstract ends with a citation of the journal
date, volume, and page numbers as well as the name of the first author.
Original
articles can be obtained by searching the web pages of the 6 journals.
Unfortunately, only BMJ allows unlimited access. All others are limited, or
require a subscription.
I
hope you find the publication interesting and of value to your practice.
Richard
T. James Jr. M.D. Editor/publisher
Practical Pointers is now in its 18th
year of publication. It is being sent each month to 40 different countries.
I
am always seeking new
“subscribers”. I will e-mail, by
attachment, each monthly issue as it becomes available during the year to
anyone supplying his or her e-mail address. Inquires to rjames6556@aol.com
There
is never any charge for this public service.
RTJ
MEDICAL
SUBJECT HEADINGS 2003
ALENDRONATE (See OSTEOPOROSIS)
ALTERNATIVE/COMPLEMENTARY
MEDICINE
ALZHEIMER’S DISEASE (SEE ALSO DEMENTIA)
AMBULATORY BLOOD PRESSURE (See HYPERTENSION)
ANGIOPLASTY (See MYOCARDIAL
INFARCTION)
ANGIOTENSIN CONVERTING
ENZYME (ACE) INHIBITORS
ANTIOXIDANT (See VITAMINS)
ATKINS DIET (See DIET)
BENIGN PROSTATIC
HYPERPLASIA (BPH)
BETA BLOCKER (See HEART FAILURE)
BRAIN INFARCT (See DEMENTIA)
CANCER
(See BREAST CANCER, PROSTATE CANCER,
CERVICAL CANCER)
CANCER OF THE CERVIX (See HUMAN
PAPILLOMA VIRUS)
CANCER OF THE ESOPHAGUS (See BARRETT’S ESOPHAGUS)
CHRONIC OBSTRUCTIVE
PULMONARY DISEASE (COPD)
COGNITIVE IMPAIRMENT (See DEMENTIA)
CONGESTIVE HEART FAILURE (See HEART FAILURE)
D-DIMER
(See VENOUS THROMBOEMBOLISM)
DIABETIC NEPHROPATHY (See DIABETES)
DIASTOLIC HEART FAILURE (See HEART FAILURE)
DIGOXIN (See HEART FAILURE)
DIURETICS (See HYPERTENSION)
DOXAZOCIN (See BENIGN PROSTATIC HYPERPLASIA)
ESTROGEN (See HORMONE REPLACEMENT THERAPY)
FINASTERIDE (See BENIGN PROSATATIC HYPERRPLASIA; PROSTATE CANCER)
GLUCOSAMINE-CHONDROITIN (See OSEOARTRITIS)
IBUPROFEN (See ASPIRIN)
INTIMA-MEDIA THICKNESS (See CARDIOVASCULAR DISEASE)
ISOLATED SYSTOLIC HYPERTENSION (See HYPERTENSION)
KILLIP CLASSIFICATION OF HEART
FAILURE (See HEART FAILURE)
LETROZOLE (See AROMATASE INHIBITOR; BREAST
CANCER)
LEWY BODIES (See DEMENTIA)
LIPIDS
(See CHOLESTEROL)
LOW-CARBOHYDRATE DIET (See DIET)
MEDITERRANEAN DIET (See DIET)
MELATONIN (See JET LAG)
MICROALBUMINURIA (See DIABETES)
NEUROMINIDASE INHIBITOR (See INFLUENZA)
NON-ALCOHOLIC FATTY LIVER
DISEASE
NONSTEROIDAL
ANTI-INFLAMMATORY DRUGS (NSAIDs)
OTTAWA ANKLE RULE (See FRACTURE)
PACEMAKER (See VASOVAGAL SYNCOPE)
PAPANICOLAOU TESTING (See SCREENING)
PATIENT’S RELATIONSHIP
WITH THEIR DOCTORS
PHYSICAL ACTIVITY (See FITNESS)
POSTMENOPAUSAL HORMONE THERAPY (See HORMONE REPLACEMEENT
THERAPY)
PREMENSTRUAL DYSPHORIC
DISORDER
PROSTATE SPECIFIC ANTIGEN (See PROSTATE CANCER)
REQUESTS FOR CLINICAL
SERVICES
SENSITIVITY, SPECIFICITY,
PREDICTIVE VALUES, AND LIKELIHOOD RATIOS
STATIN DRUGS (See CHOLESTEROL)
SUDDEN ACUTE RESPIRATORY
SYNDROME (SARS)
THROMBOEMBOLIC DISEASE (See VENOUS THROMBOEMBOLISM)
THROMBOLYTIC THERAPY (See MYOCARDIAL INFARCTION)
THROMBOSIS (See VENOUS THROMBOEMBOLISM; ANTICOAGULANT
THERAPY)
UPPER RESPIRATORY INFECTION (See ECHINACEA)
HIGHLIGHTS
AND EDITORIAL COMMENTS 2003
In early February 2003, the SAMHSA sent
a “Dear Physician” letter outlining a new, office-based approach to opioid
addiction. It represents a new era in addiction treatment.
The new treatment option is based on
buprenorphine, a partial opiate agonist/antagonist recently approved by the
FDA. Physicians can now provide opioid addiction treatment in their own
offices. It also provides access to a supportive network of treatment
specialists who can address the psychosocial needs of patients undergoing
detoxification or maintenance. Buprenorphine
has a lower potential for abuse, a lower level of physical dependence, and
weaker opioid effects than other drugs such as methadone.
1-8 ESCALATION OF DRUG USE IN EARLY-ONSET
CANNABIS USERS VS CO-TWIN CONTROLS. Associations between early cannabis use and
later drug use and abuse/dependence cannot be explained solely by common
predisposing genetic or environmental factors. Early initiation of cannabis
(before age 17) was associated with significantly increased risk of other drug
use and abuse/dependence later in life.
This is consistent with early use of marijuana having a causal role as a
risk factor.
Regardless of the mechanisms underlying
the associations, it is apparent that young people who initiate cannabis at an
early age are at heightened risk of progressing to other drug use and drug
abuse/dependence.
1-7 DIRECT-TO-CONSUMER ADVERTISING AND SHARED
LIABILITY FOR PHARMACEUTICAL MANUFACTURERS
Marketing of prescription drugs has
undergone substantial change facilitated by the regulatory environment
governing direct-to-consumer advertising. (DTCA). Physicians who write prescriptions on the request of patients who
have been influenced by DTCA, do not relinquish any of their traditional
control over prescribing
9-12 ASSESSING THE SUCCESS OF SUCCESSFUL AGING
Clinicians must learn what their patients expect and
value, and develop treatment plans that balance longevity with other facets of
life. We should determine what social roles patients most value, what features
of functioning are most important, and which strategies of treatment and
prevention will optimize the chances of success as the patient defines it.
Successful aging is possible despite disease and disability. If our concept of successful aging
includes dignity, autonomy, social engagement, and the absence of suffering, we
will be better positioned to configure our system of care to address the needs
of the elderly. Pursuing the myth of
the Fountain of Youth is not the
answer.
Success in aging is “what I say it is” and what I make
it. I will not depend on my clinician
or on the public health service to define it.
1-13 ROLE OF DRINKING PATTERN AND TYPE OF ALCOHOL
CONSUMED IN CORONARY HEART DISEASE IN MEN
Among men, consumption of alcohol at
least 3 to 4 times per week reduced risk of MI. Neither the type of beverage, nor the proportion consumed with
meals substantially altered the association.
Men who increased their alcohol
consumption by a moderate amount during the follow-up had a decreased risk of MI.
2-8 ALCOHOL
CONSUMPTION AND RISK OF STROKE: A
Meta-analysis
Heavy alcohol consumption increases risk of stroke.
Light-to-moderate consumption protects against ischemic stroke, but not against
hemorrhagic stroke.
4-5 PROSPECTIVE STUDY OF ALCOHOL CONSUMPTION AND
RISK OF DEMENTIA IN OLDER ADULTS
Compared with abstinence, consumption of 1 to 6 drinks weekly was
associated with a lower risk of dementia among older adults.
9-9 ALCOHOL USE
DISORDERS IN ELDERLY PEOPLE: Redefining An Age Old Problem In Old Age
Be
vigilant for the role of alcohol when older people present with physical and
psychiatric illness, cognitive
impairment,
and social problems. Use disorders may be more common in the elderly than you think .
Primary care clinicians should include sensitive
questions about alcohol use in their systemic review of the patient history.
10-7 SHOULD DOCTORS PRESCRIBE ALCOHOL TO ADULTS?
“There is no more emblematic standard of good health in the
United States than the food guide pyramid. It is widely recognized if not well
followed. The pyramid advises Americans to eat lots of grains and fruits and
vegetables, some meat and dairy, and a small amount of fat and sugars.”
“One day soon, it (the food pyramid) may advise adult
Americans to have a drink of beer, wine, or spirits every day as well. The idea is not as radical as it seems. ”
Epidemiological evidence from more than 100 observational
studies over the past 3 decades has shown that moderate alcohol consumption
helps prevent heart disease. Other health benefits include reduced risk for
ischemic stroke, peripheral vascular disease, and diabetes. Risk of heart
disease among moderate drinkers is 35% or so lower than in non-drinkers.
“Alcohol clearly has a sizable effect, and it’s not so easy to ignore that.”
The policy makers at the U.S. Department of Health and
Human Services are reconsidering their stance on alcohol—which in the past has
consisted of mentioning the health benefits of alcohol while emphasizing the
adverse effects—as they update the U.S. dietary guidelines. With the policy
experts talking ever more seriously about endorsing moderate drinking, is it
time for physicians to consider selective prescription of alcohol for patients?
“For appropriate patients who do not drink, or do so only
occasionally, and who wish to do so, encouraging a glass of wine or other
alcoholic beverage with dinner every night may be the best advice you can give
them.”
Some
authorities urge caution. Most current guidelines recommend
moderate drinking only for people who already drink, and urge abstainers not to start drinking for their health.
Some physicians now believe clinicians should discuss alcohol consumption with
all patients and inform those without contraindications of the benefit of
regular moderate consumption.
4-9 ALDOSTERONE BLOCKADE AND HEART FAILURE
“The addition of aldosterone antagonists to the
regimens of patients with left ventricular systolic dysfunction and ongoing
symptoms of heart failure despite optimal treatment with ACE inhibitors and
beta-blockers can substantially reduce overall mortality and the rate of sudden
death.”
ALTERNATIVE/COMPLEMENTARY MEDICINE
12-9 EFFICACY AND SAFETY OF ECHINACEA IN TREATING
UPPER RESPIRATORY TRACT INFECTIONS IN CHILDREN
Echinacea is a herbal remedy widely used
for prevention and treatment of upper respiratory infections (URIs). It is one of the most commonly
used herbal remedies in the USA . Three species of echinacea are used.
Beneficial effects are thought to be due to its “immunomodulating” activity,
most notably macrophage activation and enhanced neutrophil phagocytosis.
This study postulated that treatment with E purpurea would result in at least a
1.5- to 2-day reduction in duration of URIs in children, and that symptoms
would be less severe than in patients receiving placebo.
The preparation used in this study was not effective in treating URIs in
children. After the trial was completed, parents could not guess correctly whether their child had taken echinacea or
placebo. “Our results do not support
the use of echinacea for treatment of URIs in children.” Its use was associated with an increased
risk of rash.
This study was supported by a grant from
the National Center for Complementary and Alternative Medicine, Bastyr
University (an alternative medicine institution) and National College of
Naturopathic Medicine, Portland Oregon.
It
continues to amaze me that so many persons take unstandardized and unproven
nostrums and give them to their children. I am sure devotees will fault this
study. They will remain convinced that echinacea is beneficial.
7-11 EFFECT OF NON-STEROIDAL ANTI-INFLAMMATORY
DRUGS ON RISK OF ALZHEIMER’S DESEASE
The study lends support to the hypothesis that NSAIDs may protect against
the development of Alzheimer’s disease. They are too toxic to be used for this
purpose in large numbers of patients.
This provocative study suggests that we
may be on the way to developing safe preventive measures.
10-14 EXERCISE PLUS BEHAVIORAL MANAGEMENT IN
PATIENTS WITH ALZHEIMER DISEASE.
Improving physical conditioning in
patients with AD may extend their independent mobility and enhance their
quality of life despite progression of the disease. Even the oldest adults can
improve cardiovascular function and increase flexibility, balance, and
strength.
A number of studies link AD with physical deterioration.
When compared with age-matched controls, AD patients show more signs of
undernutrition, higher risk of falls and fractures, and a more rapid decline in
mobility. Reduced muscle mass has been associated with loss of independence.
In this study exercise training improved physical health
and lessened depression in patients with AD,
10-16 PROGNOSTIC VALUE OF MYELOPEROXIDASE IN
PATIENTS WITH CHEST PAIN
Clinical criteria, ECG criteria, and conventional
laboratory tests, including troponin T, often do not adequately predict the
risk of cardiovascular events in patients presenting with acute coronary
syndromes.
C-reactive protein and other markers have been advocated as
a more accurate means of gauging risk,
but
additional tools are needed to predict vulnerability of coronary arteries to
major events in the near term. Myeloperoxidase is an excellent candidate. It
predicts cardiovascular risks independently of C-reactive protein and other
markers of inflammation.
“Our findings suggest that myeloperoxidase serves as a
marker of the vulnerable plaque and one that
can be
used to identify patients at imminent
risk for major adverse cardiac events, independently of evidence of myocardial
necrosis.”
A single measurement of myeloperoxidase independently
predicted early risk of myocardial infarction, as well as the risk of major
adverse cardiac events in the ensuing 30 days and 6 months.
ANGIOTENSIN CONVERTING ENZYME (ACE)
INHIBITORS
Combined ACE-I and A II-I therapy safely
retarded progression of non-diabetic renal disease more effectively than either
drug alone.
Initiation of antihypertension treatment with ACE
inhibitor in older men appeared to lead to better outcomes than diuretics
despite similar reductions of BP. Patients often required 2 or more drugs.
NNT to benefit one male patient over 1
year = 270. No benefit in females.
Cardiac cachexia is common in chronic
HF. It independently predicts a poor outcome. This may assist decisions for
Hospice care. Enalapril delays development of cardiac cachexia in some
patients.
7-13 INTERACTION OF SPIRINOLACTONE WITH ACE
INHIBITORS OR ANGIOTENSIN-RECEPTOR BLOCKERS
Spirinolactone
and ACE inhibitors act synergistically or additively to increase plasma
potassium levels. Toxic and even lethal concentrations may result.
Spirinolactone is established as an important additive in therapy for patients
with severe heart failure. The dose should not exceed 25 mg daily, and in some
patients should be less.
Among patients with stable CAD without apparent heart failure, the angiotensin
converting enzyme inhibitor, perindopril (Aceon)
improved outcomes. This was in addition to use of other preventive drugs. [NNT(4 years to benefit one) = 50]
ACE inhibitors have been shown to have the broadest
impact of any drugs in cardiovascular medicine, reducing the risk of death,
myocardial infarction, stroke, diabetes, and renal impairment. They benefit
patients with heart failure, post myocardial infarction left ventricular
dysfunction, peripheral vascular disease, diabetes, stroke, and transient
ischemic attacks.
As long-term therapy, perindopril is expensive. It has
not been compared with less expensive ACE inhibitors (eg, enalapril) which may
be just as effective.
ACE inhibition
is underused in primary care practice.
Angiotensin-converting-enzyme inhibitors (ACE-I) do not completely block
production and effects of angiotensin II. Likewise, angiotensin-receptor
blockers (ARB) do not completely block
angiotensin II. But, they do act differently. Investigators have speculated
that adding the two would produce greater benefits than either one used alone.
In this study, however, use of the two
drugs together did not benefit any more than either used alone. Valsartan is as
effective as captopril (but not more effective) as measured by risk of death in
patients who are at high risk for cardiovascular events after a myocardial
infarction. The combination increased adverse effects without improving survival.
I abstracted this study because it contrasts with
other studies reported in Practical
Pointers. Doubt remains about the efficacy of combined ACE inhibitors and
ARBs. See “Effects of Candesartan on Mortality and Morbidity in Patients with
Chronic Heart Failure” Practical Pointers September 2003. The
study reported a slight benefit when candesartan was added to ACE inhibitors.
(NNT = 25 to 50) Hyperkalemia,
hypotension, and increased creatinine levels occurred more commonly in the
combined group.
I believe primary care clinicians should avoid the
combination until clarification is available. ARB may be used when ACE
inhibitors are not tolerated. RTJ
1-9 PROPHYLACTIC TREATMENT OF MIGRAINE WITH AN
ANGIOTENSIN-II RECEPTOR BLOCKER
In this study, the angiotensin II
blocker, candesartan, provided effective migraine prophylaxis with tolerability
comparable to that of placebo.
Combined ACE-I and A II-I therapy safely
retarded progression of non-diabetic renal disease more effectively than either
drug alone.
7-13 INTERACTION OF SPIRINOLACTONE WITH ACE
INHIBITORS OR ANGIOTENSIN-RECEPTOR BLOCKERS
Spirinolactone and ACE inhibitors act
synergistically or additively to increase plasma potassium levels. Toxic and
even lethal concentrations may result. Spirinolactone is established as an
important additive in therapy for patients with severe heart failure. The dose
should not exceed 25 mg daily, and in some patients should be less.
9-6 EFFECTS OF CANDESARTAN ON MORTALITY AND
MORBIDITY IN PATIENTS WITH CHRONIC HEART FAILURE
ACE inhibitors have been shown to have the broadest
impact of any drug in cardiovascular medicine, reducing the risk of death,
myocardial infarction, stroke, diabetes, and renal impairment. They benefit
patients with heart failure, left ventricular dysfunction, peripheral vascular
disease, diabetes, stroke, and transient ischemic attacks.
Candesartan, blocks angiotensin II at
the cellular level. Given to patients
with heart failure in addition to
other drugs (including ACE inhibitors) it was associated with reduced
cardiovascular deaths and hospital admissions for heart failure.
Reducing
angiotensin II levels is a basic therapy in cardiovascular disease. ACE
inhibitors have been the standard. Addition of an angiotensin II blocker may
benefit slightly. They should be used when the patients cannot tolerate ACE
inhibitor.
Angiotensin-converting-enzyme inhibitors (ACE-I) do not completely block
production and effects of angiotensin II. Likewise, angiotensin-receptor
blockers (ARB) do not completely
block angiotensin II. But, they do act differently. Investigators have
speculated that adding the two would produce greater benefits than either one
used alone.
In this study, however, use of the two
drugs together did not benefit any more than either used alone. Valsartan is as
effective as captopril (but not more effective) as measured by risk of death in
patients who are at high risk for cardiovascular events after a myocardial
infarction. The combination increased adverse effects without improving
survival.
I abstracted this study because it contrasts with
other studies reported in Practical
Pointers. Doubt remains about the efficacy of combined ACE inhibitors and
ARBs. See “Effects of Candesartan on Mortality and Morbidity in Patients with
Chronic Heart Failure” Practical Pointers September 2003. The
study reported a slight benefit when candesartan was added to ACE inhibitors.
(NNT = 25 to 50) Hyperkalemia,
hypotension, and increased creatinine levels occurred more commonly in the combined
group.
I believe primary care clinicians should avoid the
combination until clarification is available. ARB may be used when ACE
inhibitors are not tolerated. RTJ
1-1 WHY DO GENERAL PRACTITIONERS PRESCRIBE
ANTIBIOTICS FOR SORE THROAT?
Describing the difference between
“Evidence Based Medicine” and the “Real World” of practice. Despite the power
of EBM, there are many instances and reasons for deviation.
Best evidence indicates that antibiotics
are of minimal or no benefit for sore throat, acute bronchitis, the common
cold, and otitis media. Antibiotics continue to be commonly used for these
conditions. This is potentially inappropriate
prescribing.
This has prompted the use of delayed (or
“as needed”, or “if”) prescriptions. These prescriptions
are
written with the proviso that they are not to be used immediately—only later if
symptoms do not improve in a few days. Use of a delayed prescription should be
restricted to patients who request antibiotics or for whom the doctor thinks
one is not immediately indicated.
A randomized trial in 1997 gave
prescriptions for antibiotics for respiratory infections: 1) to be filled immediately,
or 2) to be filled after 3 days, or 3) no antibiotic prescription.
The immediate group filled 99%.
The delayed group filled 31%.
In the no-prescription group,
13% filled an antibiotic prescription after a return visit to
the physician.
The reduction in use of antibiotics for
upper respiratory infections through using delayed prescriptions is as
effective, and in many cases, more effective than educational projects.
Emboli of atrial origin are larger than
average. The brain infarcts they
produce are more disabling and lethal.
Among patients with non-valvular AF, the degree of
anticoagulation at admission for stroke was associated with risk of disability and death.
Anticoagulation that resulted in an INR of 2.0 or greater reduced frequency and
severity of ischemic stroke and risk of death. This is evidence against INR
targets below 2.0
Risk of hemorrhagic stroke did not
increase until INR was 4.0 or above.
INR below 2.0 and aspirin protect against stroke less
effectively than INR 2.0 to 3.0, but
are superior to use of no anticoagulant. Aspirin is adequate prophylaxis
in patients considered at low risk for thromboembolic stroke. Eventually almost
all patients with AF will become high risk due to age and co-morbidity. As age
progresses, risk of bleeding from warfarin increases. This dilemma must be
solved on an individual basis. Patients accepting warfarin must be carefully
controlled at a stable INR around 2.5.
“Our results
provide further support for anticoagulation to achieve an INR of 2.0 or greater
(eg, 2.5) in patients with non-valvular atrial fibrillation.”
9-2 ORAL XIMELAGATRAN FOR SECONDARY PROPHYLAXIS
AFTER MYOCARDIAL INFARCTION
In patients with a recent MI, long term treatment with
ximelagatran, combined with aspirin, was more effective than aspirin alone in
reducing frequency of major cardiovascular events. [NNT (for 6 months to benefit one) = 33]
Ximelagatran is the first of a
new class of oral direct-thrombin
inhibitors under investigation. It is rapidly metabolized to its active
form, melagatran. It is stable over time. Its metabolism is unaffected by age,
sex, body weight, or ethnic origin. It is not affected by the hepatic
cytochrome P450 enzyme system, thus providing a low potential for drug-drug
interactions. There are no relevant
food or alcohol interactions. “Melagatran’s
pharmacokinetics are unchanged and the pharmacodynamic properties show only
minor additive effects when oral ximelagatran and acetylsalicylic acid are
given concomitantly.” Ximelagatran
has undergone extensive assessment in patients with venous thromboembolism and
atrial fibrillation. It has a rapid onset of action, achieves a peak level
within 2 hours, and has a half-life of 4 hours. It is administered twice daily.
There is no need of monitoring and dose
adjustments. (Monitoring of liver and
kidney function is required. RTJ) Ximelagatran is primarily excreted by the
kidney. Data on patients with kidney dysfunction are limited.
With the 24 mg BID dose, the bleeding rate was low,
and high concentrations of alanine amino transferase occurred less frequently
(7%).
“It is good news that the more than half
century wait of new and improved oral antithrombotics finally appears to be
ending.”
10-2 TREATING THROMBOSIS IN THE 21ST
CENTURY
Now, a minimal anti-thrombin-binding unit of heparin, a
pentasaccharide called fondaparinux, has been synthesized and is undergoing
clinical trials. Fondaparinux enhances anti-thrombin activity. It is a specific
inhibitor of activated factor X (Xa). It requires subcutaneous administration.
It can be given once a day on a weight basis. It does not require laboratory
monitoring.
A second new anticoagulant (melagatran)
took its cue from the leach which produces a direct thrombin inhibitor
(hirudin). Hirudin acts independently
of anti-thrombin and other plasma proteins. The discovery of hirudin led to
other direct thrombin inhibitors, one of which is melagatran. Melagatran can
also neutralize clot-bound thrombin. Chemical modification (to “ximelagatran”)
allows better oral absorption. It is the first new oral anticoagulant since
warfarin. Like fondaparinux, it does not require laboratory monitoring.
Once-daily fondaparinux without monitoring is at least as
effective and safe as adjusted-dose IV unfractionated heparin in the initial
treatment of hemodynamically stable patients with pulmonary embolism.
“Because of its simplicity, once-daily
subcutaneous fondaparinux without anticoagulation monitoring could replace
intravenous administration of unfractionated heparin in most patients.”
Fixed dose ximelagatran 36 mg bid, administered without
coagulation monitoring, was significantly more effective than warfarin in
prevention of thromboembolism after knee replacement. Safety was similar “It could therefore be considered an
alternative to other thromboprophylactic agents.”
10-5 SECONDARY PREVENTION OF VENOUS
THROMBOEMBOLISM WITH ORAL DIRECT THROMBIN INHIBITOR XIMELAGATRAN
Ximelagatran is a direct thrombin
inhibitor undergoing active investigation as an anticoagulant. It is given in a
fixed dose daily, and needs no monitoring.
Beginning and continuing extended secondary prevention of
VTE with ximelagatran 24 mg bid for an additional 18 months after 6 months of
standard anticoagulation effectively prevented recurrences. [NNT = 10]
The incidence of major hemorrhage was low and similar to
placebo. Ximelagatran was equally
effective in subgroups that had risk factors for recurrence—previous VTE,
proximal deep VTE, and pulmonary embolism.
The fixed-dose ximelagatran was well
tolerated without monitoring measures of coagulation.
In patients with venous thromboembolism (VTE), there is a perception that the clinical impact of
preventing recurrent VTE and possible fatal pulmonary embolism outweighs the
risk of bleeding associated with long-term anticoagulation..
The subgroup of patients with idiopathic
(unprovoked) VTE, and VTE associated with factor V Leiden, prothrombin
mutations, and deficiencies of protein C and protein S make up about half of
the thousands of patients in whom symptomatic VTE is diagnosed each year in the
USA.
The optimal duration of anticoagulation
is still unclear.
This systematic review of randomized,
controlled trials and prospective cohort studies
(10
757 patients; 4373 patient-years) investigated patients with confirmed
idiopathic VTE. All received oral anticoagulant therapy (target INR--2.0 to
3.0) for at least 3 months. Nine of 33 studies reported use for over 3 months
(6 to 24 months).
The chances of a major bleed per year of anticoagulation were 7 in
100 patients with 1 in 1000 chance of fatality, and about 1 chance in 100 of an
intracranial bleed.
The primary care clinician must make
some attempt to balance the risk of bleeding vs the benefits of
anticoagulation
in each individual patient. (I know of no
means of doing this beyond “clinical judgment”. RTJ )
Letrozole, an aromatase inhibitor, begun after 5-years
of tamoxifen had been completed, significantly improved disease-free survival.
Aromatase is the enzyme which converts the androgenic substrates,
androstenedione and testosterone, into estradiol. Letrozole (Femara) is one of several new aromatase
inhibitors (a third generation). This drug binds to the aromatase and almost
completely inactivates it, thus providing maximal endocrine control of breast
cancer (BC).
The aromatase inhibitors are challenging tamoxifen,
the previous gold standard for treatment of postmenopausal women with
estrogen-receptor-positive BC. In
advanced BC, letrozole is clearly superior to tamoxifen as first-line therapy. Aromatase inhibitors are also being
considered in chemoprevention, a strategy in which tamoxifen has already been
shown to reduce incidence of BC.
Tamoxifen blocks the binding of estradiol to the BC
cells. It has dual effects which are complex, both antagonistic and agonistic.
After 5 years of treatment its agonistic effects may predominate. Aromatase
inhibitors do not have agonistic effects.
There was also a reduction in the frequency of new
primary BC in the contralateral breast (relative
reduction
of 46%).
12-6 INTRA-ARTICULAR HYALURONIC ACID IN TREATMENT
OF KNEE ARTHRITIS
“Based on the findings of this
meta-analysis, intra-articular hyaluronic acid has, at best, modest
efficacy
in the treatment of knee osteoarthritis. This effect . . . “is equivalent to
the effect of NSAIDs over that of acetaminophen, an effect that itself remains
controversial.” .” “Our findings
suggest the controversy surrounding the efficacy of intra-articular hyaluronic
acid is justified and the best evidence does not support its efficacy.”
At least 17 of the 22 trials were
industry sponsored. Others have suggested that findings from
industry-sponsored
trials compared with those that were otherwise funded showed that research
funded by pharmaceutical companies was more likely to have outcomes favoring
the sponsor.
All 22 studies reported improvement of
pain in the intra-articular placebo groups. Placebo injections may have
efficacy for treating knee OA. The investigators calculated that
intra-articular placebo accounted for 79% of the efficacy of intra-articular
hyaluronic acid.
“This supports our hypothesis that the majority of the effect of
intra-articular hyaluronic acid is an
intra-articular
placebo effect.”
Publication
bias may overestimate the effect. Compared with lower-molecular-weight
hyaluronic acid, the higher-molecular weight hyaluronic acid may be more
efficacious, but heterogeneity of studies limits definitive conclusions.
I doubt this study will deter
enthusiasts from using HA. Individual patients who have apparently obtained
relief may insist on continuing.
The only way an individual’s response
can be accurately determined is by an N-of-one trial.
I
doubt this would be feasible considering the ethical issues involved.
2-5 EFFECT OF
IBUPROFEN ON CARDIOPROTECTIVE EFFECT OF ASPIRIN
Ibuprofen negates the protective effect
of low dose aspirin. Use another NSAID.
Compared with placebo, a daily dose of 325 mg aspirin
reduced risk of adenoma development in patients with a history of surgery for
CRC. (High risk patients.)
3-12 A RANDOMIZED TRIAL OF ASPIRIN TO PREVENT
COLORECTAL ADENOMAS
Low-dose aspirin had a moderate chemoprotective effect
on adenoma formation.
3-13 ASPIRIN AND PREVENTION OF COLORECTAL CANCER
Among persons with a history of adenomas or CRC the
number of recurrences of adenomas prevented by aspirin (secondary prevention) would be higher than the number of episodes
of bleeding. However, the cumulative clinical importance of bleeding probably
exceeds that of surrogate neoplasm-related outcomes, especially when the effect
of colonoscopic surveillance is taken into account.
If aspirin is used for primary prevention of CRC, it would have
to be given for 10 to 20 years, the time it takes for CRC to develop. The
cumulative adverse effects of aspirin over this time outweigh any benefit in
prevention of CRC, particularly when prevention by screening for CRC is
considered. Long-term use of aspirin for primary prevention of CRC is not
cost-effective. It does not obviate the
need for screening and surveillance.
Aspirin does reduce risk of recurrent
colorectal neoplasia. Whether aspirin has a role in preventing colorectal
cancer and whether it can be used to decrease the required frequency of
screening or surveillance must await results of clinical trials.
Stroke risk varies greatly in AF patients. This study
sought to derive and validate a simple and easily applied clinical rule to
identify individuals with non-valvular AF whose stroke risk while taking
aspirin is low enough that oral anticoagulation is not necessary.
Irrespective of age, a patient with non-valvular AF without
previous stroke or TIA, without hypertension, without symptomatic coronary
heart disease or heart failure, and without diabetes can take aspirin for
stroke prevention and would not likely benefit from anticoagulation.
Use of the rule would prevent almost one quarter of AF
patients, regardless of age, to avoid anticoagulation. Sixteen percent of patients over age 75 were
classified as low risk and thus would not be exposed to the risks of
anticoagulation.
3-8 EARLY INTERVENTION WITH BUDESONIDE IN MILD
PERSISTENT ASTHMA
Long-term, once-daily low-dose inhaled
budesonide decreased the risk of severe exacerbations and the need for systemic
corticosteroids and improved asthma control in patients with mild, persistent
asthma of recent onset.
3-9 INHALED GLUCOCORTICOIDS VERSUS LEUKOTRIENE
RECEPTOR ANTAGONIST AS SINGLE AGENT ASTHMA TREATMENT
Anti-leukotrienes as single agents were less effective than inhaled corticosteroids
in the treatment of adults with mild to moderate asthma.
Telephone consultations enabled more patients with
asthma to be reviewed. There was no apparent clinical disadvantage or loss of
satisfaction. They may be an efficient option for primary care practice.
1-15 DRUG
ELUTING STENTS IN VASCULAR INTERVENTION
Immunosuppressive
agents (which inhibit tumor-cell growth) may also inhibit the benign tissue
proliferation characterizing intimal hyperplasia. Several immunosuppressants
have been tested for potential to inhibit restenosis. Stents coated with the
agents are becoming available. Local drug delivery achieves higher tissue
concentrations of drugs, while producing no systemic effects. This is
associated with a marked reduction in the risk of re-stenosis.
“The
clinical impact of the elimination of restenosis may influence the approach to
coronary artery disease, the future of cardiac surgery, and health-care
economics.”
8-8 EMERGING RISK FACTORS FOR ATHEROSCLEROTIC
VASCULAR DISEASE.
This critical review highlights 4 emerging risk
predictors: C-reactive protein, Lipoprotein (a), Fibrinogen, and Homocysteine.
“Their optimal
use in routine screening and risk stratification remains to be determined.”
“The explanatory power of the major established cardiovascular risk factors has been
systematically underestimated.” (See
previous abstract.)
Primary
care clinicians and their patients have not even begun to assess, prevent, and
treat the established major, modifiable risk factors. Until we do, I believe we need no more risk factors.
We will, with interest, however, follow
the basic science investigations aimed at determining the best mix of risk
factors on which to base clinical interventions.
11-4 STARTING EARLIER TO PREVENT HEART DISEASE.
Two studies reported in the November 5 issue of JAMA measured carotid artery
intima/media thickness (IMT) in young adults (age 24 to 37). LDL-cholesterol
and BMI had been measured in childhood, up to 22 years earlier. Higher
childhood levels of both predicted increased adult carotid IMT. In one study,
systolic BP and smoking in adolescence also predicted increased IMT. (The
higher the carotid IMT, the greater the extent of coronary atherosclerosis.)
It is clear that risk factors begin to matter during
adolescence, the age range during which fatty streaks in the coronary arteries
begin to be converted to raised lesions, and when high-risk populations begin
to diverge from low-risk populations.
“It may be possible that risk factors in the early teen-age years are
associated with permanent damage to the arterial wall.”
Assessing risk factors in youth is easy and
inexpensive. Cholesterol and other risk factors do matter during adolescence.
It may now be time to reconsider the age at which measurement of cholesterol
and life-style changes should begin. The difficulty of changing life styles in
teenagers, however, should not be underestimated. Physicians caring for
children and adolescents should be sure their patients and their parents know
it is beneficial and safe to promote and maintain a healthy life style.
Changing ingrained life-style habits in
teen-agers is almost impossible. Parents must set the example and begin
lifetime habits of their children at a pre-teen age.
Stroke risk varies greatly in AF patients. This study
sought to derive and validate a simple and easily applied clinical rule to
identify individuals with non-valvular AF whose stroke risk while taking
aspirin is low enough that oral anticoagulation is not necessary.
Irrespective of age, a patient with non-valvular AF
without previous stroke or TIA, without hypertension, without symptomatic
coronary heart disease or heart failure, and without diabetes can take aspirin
for stroke prevention and would not likely benefit from anticoagulation.
Use of the rule would prevent almost one quarter of AF
patients, regardless of age, to avoid anticoagulation. Sixteen percent of patients over age 75 were
classified as low risk and thus would not be exposed to the risks of
anticoagulation.
This risk score for embolic stroke was derived from 5
risk predictors: advancing age, female
sex, increasing systolic BP, prior stroke or TIA, and diabetes. The score can
be used to estimate absolute risk of
stroke (5% to 75% over 5 years) and help to negotiate treatment decisions with
patients with AF at the time they are first diagnosed. . Risk may be stratified into mild, moderate
or severe.
Although some physicians and patients may more readily
accept and act on a numerical risk prediction,
I
believe primary care clinicians can just as accurately judge risk without
creating a numerical 5-year “risk”. Most patients will eventually end up
receiving anticoagulation. It is nevertheless important to spare those at low
risk from the potential adverse effects of warfarin therapy and use aspirin
instead. Patients with AF, but without structural heart disease, (including no
hypertension) are at relatively low risk, especially if they are under age 65.
To anticoagualate or not anticoagualate is a difficult
and important decision. It remains a clinical-judgment call. For each patient,
clinicians must strike an acceptable balance between risk of ischemic stroke
and bleeding. In the absence of an absolute or important relative
contraindication, the data seem compelling that warfarin therapy should be
offered to most patients with AF. The difficulty is to know what threshold of
stroke risk is low enough so that the potential risk of warfarin therapy
outweighs its potential benefits. For
most patients the potential benefits of stroke prevention will outweigh the
potential risks of bleeding secondary to warfarin.
An article (Annals
Internal Medicine April 28 , 2003; 163: 936-43; Practical Pointers April 2003) differs somewhat in suggesting that up to
1/3 of patients with AF can be classified as low-risk and treated with aspirin.
Emboli of atrial origin are larger than
average. The brain infarcts they
produce are more disabling and lethal.
Among patients with non-valvular AF, the degree of
anticoagulation at admission for stroke was associated with risk of disability and death.
Anticoagulation that resulted in an INR of 2.0 or greater reduced frequency and
severity of ischemic stroke and risk of death. This is evidence against INR
targets below 2.0
Risk of hemorrhagic stroke did not
increase until INR was 4.0 or above.
INR below 2.0 and aspirin protect against stroke less
effectively than INR 2.0 to 3.0, but
are superior to use of no anticoagulant. Aspirin is adequate prophylaxis
in patients considered at low risk for thromboembolic stroke. Eventually almost
all patients with AF will become high risk due to age and co-morbidity. As age
progresses, risk of bleeding from warfarin increases. This dilemma must be
solved on an individual basis. Patients accepting warfarin must be carefully
controlled at a stable INR around 2.5.
“Our results
provide further support for anticoagulation to achieve an INR of 2.0 or greater
(eg, 2.5) in patients with non-valvular atrial fibrillation.”
Ximelagatran is a direct thrombin inhibitor which is
given orally.. Its pharmacokinetic profile is predictable and stable overtime.
It has low potential for drug-drug interactions and does not require monitoring
or dose adjustment.
Fixed dose ximelagatran was at least as effective as
well-controlled warfarin for prevention of
stroke and systemic embolism. It is much easier to use.
Practical Pointers has abstracted several articles on
the new oral anticoagulant ximelagatran. (See October 2003 issue.)
Ximelagatran looks very promising.
9-11 RISK OF ADENOCARCINOMA IN BARRETT’S
ESOPHAGUS
“Patients with Barrett’s oesophagus are at low risk of
oesophageal adenocarcinoma. This risk is almost
exclusively
in patients with specialized intestinal metaplasia.”
“Up to 8 years after diagnosis we found
no increased risk of malignancy with time.”
Surveillance of patients with BE at a risk of
malignant transformation of 1% per year may be cost effective,
but
only in men over age 70. This questions
the value of universal endoscopic screening for cancer in patients with BE.
Primary care clinicians in the USA refer
patients with BE to gastroenterologists. They will usually advise periodic
endoscopic screening .
BENIGN PROSTATIC HYPERPLASIA (BPH)
This study assessed the long-term
effects of diazoxide (an alpha blocker) alone, finasteride (a reductase
inhibitor) alone, and the combination on clinical progression of BPH. It concluded that long-term therapy with
combined drugs reduced the risk of clinical progression significantly more than
either drug alone.
The number needed to treat by combined
therapy over 5 years was 8, vs 14 to 15
for the drugs used alone.
Risk of acute retention and need for
invasive therapy were reduced by finasteride but not by doxazocin.
The risk of overall clinical progression
increased with increasing baseline PSA levels and prostate volume in the
doxazocin group, but not in the
finasteride or combination group. No
alpha blocker stops the progression of prostate size. Finasteride reduces circulating dihydro-testosterone levels by
about 80%; PSA levels by 50%; and prostate size by 20%. Reductase inhibitors do
not act rapidly, and often require 6 months to reduce prostate size.
Current initial therapy in most cases consists of an
alpha blocker given alone. It acts rapidly to relieve symptoms. In the current
study, clinical progression occurred in only 17% of men in the placebo group.
In men with a low PSA and modest prostate size, progression of BPH may be slow
and use of a reductase inhibitor may be delayed. The study does support dual
use in men whose symptoms progress during monotherapy, or in men at high risk
of progression. (PSA over 4 mg/mL or prostate volume more 40 mL on ultrasound).
11-10 END-OF-LIFE CARE AND THE EFFECTS OF
BEREAVEMENT ON FAMILY CAREGIVERS OF PERSONS WITH DEMENTIA
Caregivers in this study showed remarkable resilience
in adapting to the death of their relatives. A large
majority
reported feeling relieved by the death, although persons whose relatives were
institutionalized did not show as rapid a recovery from depressive symptoms.
This suggests that relief from providing daily care did not alone account for
the caregivers’ recovery from bereavement.
Investments in resources for intervention and support
may have the largest benefit when they are
applied
to caregivers and patients in the period immediately preceding the patient’s
death. When caregivers know that their relative is on a trajectory toward
death, and when they are aware of the patient’s disability and suffering, they grieve for the loss of the patient
before the death.
Clinicians should view bereavement not only as a
phenomenon that affects caregivers after the death, but
also
as one that affects many caregivers before the death occurs.
4-4 MAMMOGRAPHIC SCREENING FOR BREAST CANCER.
Eight trials have been published. In patients between
ages 50 and 69, all reports of studies comparing screening with no screening
showed protective effects of screening—a statistically significant 20 to 35
percent reduction in mortality from BC.
The downside: False positive results necessitate
further investigation. Nationally, an average of 11% of screening mammograms are read as abnormal. BC is subsequently
found in about 3% of these women ( 0.3% of all mammograms). Thus, a woman has
about a 10% chance of a false positive result with each mammogram. Because
women are screened repeatedly, the risk of a false positive increases over
time. One study estimated that, after 10 mammograms, about half of women age 40
to 64 will have had a false positive leading to needle biopsy or open biopsy in
about 20%. The malpractice climate in the USA may work to increase the numbers
of false positive reports.
8-1 BREAST CANCER AND HORMONE-REPLACEMENT
THERAPY IN THE MILLION WOMEN STUDY
This remarkable, country-wide study confirms that
current use of HRT is associated with increased risk of incident and fatal BC.
Between 1996 and 2001, one half of the million women age 50-64 in this UK
cohort were using HRT.
The risk is substantially less for estrogen-alone than
for E-P combinations.
Use of HRT by women aged 50-64 in the UK over the past
decade is estimated to have resulted in 20 000 extra cases of BC; 15 000 of
these associated with E-P use; 5000
with use of estrogen alone. (Ie,
progestins are the major culprit.)
Women who are presently taking estrogen-progestin may
be told there is one additional chance in 150 of an invasive BC over 5 years;
and one additional chance in 800 if they are taking estrogen alone.
Risk increases with duration of use. Past users (5 or
more years previously) were not at increased risk.
Letrozole, an aromatase inhibitor, begun after 5-years
of tamoxifen had been completed, significantly improved disease-free survival.
Aromatase is the enzyme which converts the androgenic substrates,
androstenedione and testosterone, into estradiol. Letrozole (Femara) is one of several new aromatase
inhibitors (a third generation). This drug binds to the aromatase and almost
completely inactivates it, thus providing maximal endocrine control of breast
cancer (BC).
The aromatase inhibitors are challenging tamoxifen,
the previous gold standard for treatment of postmenopausal women with
estrogen-receptor-positive BC. In
advanced BC, letrozole is clearly superior to tamoxifen as first-line
therapy. Aromatase inhibitors are also
being considered in chemoprevention, a strategy in which tamoxifen has already
been shown to reduce incidence of BC.
Tamoxifen blocks the binding of estradiol to the BC
cells. It has dual effects which are complex, both antagonistic and agonistic.
After 5 years of treatment its agonistic effects may predominate. Aromatase
inhibitors do not have agonistic effects.
There was also a reduction in the frequency of new
primary BC in the contralateral breast (relative
reduction
of 46%).
Has 3 key features:
1) Intense preoccupation with
body weight and shape; 2) Repetitive
episodes of binge eating--uncontrollable eating a large quantity of food in a
defined period—usually less than 2 hours;
3) Routinely taking extreme measures to prevent weight gain: self
induced vomiting, fasting, exercise, and misuse of laxatives and diuretics.
Some patients take up to 50 laxative pills per day. Severe constipation with a
laxative-dependence syndrome may result.
Anorexia nervosa differs. Patients with BN maintain a
normal weight.
The challenge for primary care clinicians is to
suspect and recognize BN in select young women who present with vague symptoms,
anxiety and depression. The clinical
clues cited may help. A metabolic package might very well reveal a metabolic
alkalosis.
“Hypokalemia in an otherwise healthy young woman is
highly specific for BN.”
1-8 ESCALATION OF DRUG USE IN EARLY-ONSET
CANNABIS USERS VS CO-TWIN CONTROLS.
Associations between early cannabis use
and later drug use and abuse/dependence cannot be explained solely by common
predisposing genetic or environmental factors. Early initiation of cannabis
(before age 17) was associated with significantly increased risk of other drug
use and abuse/dependence later in life.
This is consistent with early use of marijuana having a causal role as a
risk factor.
Regardless of the mechanisms underlying
the associations, it is apparent that young people who initiate cannabis at an
early age are at heightened risk of progressing to other drug use and drug
abuse/dependence.
1-3 MULTIFACTORIAL INTERVENTION AND
CARDIOVASCULAR DISEASE IN PATIENTS WITH TYPE 2 DIABETES
A targeted long-term intensive
intervention aimed at multiple risk factors (hypertension, dyslipidemia,
microalbuminuria) in patients with DM-2 and microalbuminuria reduced the risk
of cardiovascular and microvascular events by about 50%.
In the elderly, vaccination against influenza was associated with large
reductions in numbers of hospitalizations from heart disease, cerebrovascular
disease, as well as pneumonia and influenza. Risk of death was reduced by about
50%.
Flu vaccination is one of the most
cost-effective health interventions. Primary care clinicians bear
responsibility for increasing uptake by the general population.
Cereal fiber consumption (equivalent to
2 slices of whole grain bread) in later life was associated with lower risk of
incident CVD.
6-1 A STRATEGY TO REDUCE CARDIOVASCULAR DISEASE
BY MORE THAN 80%
A proposed pill, to be taken by everyone, contains low
doses of a statin drug, 3 antihypertension drugs, folic acid and aspirin.
The authors calculate that one third of people taking
the pill from age 55 would benefit, gaining on average 11 years of life free
from an ischemic heart disease event or stroke.
“The preventive strategy is radical.” It
is time to discard the view that risk factors need to be measured and treated
individually if found to be ‘abnormal’. Instead, it should be recognized that
in Western society the risk factors are high in all of us, so everyone is at
risk.”
6-11 USE OF ANTIOXIDANT VITAMINS FOR THE
PREVENTION OF CARDIOVASCULAR DISEASE
A lack of beneficial effect was seen consistently for
various doses of these two vitamins in diverse populations. The routine use of
vitamin E is not supported. The use of beta carotene is associated with a small
but significant excess of all-cause mortality and cardiovascular death.
8-9 CARDIOVASCULAR RISK FACTORS AND INCREASED
CAROTID INTIMA-MEDIA THICKNESS IN HEALTHY YOUNG ADULTS
Atherosclerosis is a slowly progressive process
possibly starting at a young age. Preventive measures taken early in life might
postpone the development of atherosclerosis and decrease risk of clinical
cardiovascular disease (CVD).
Unfavorable cardiovascular risk factors (cigarette
smoking, diabetes, dyslipidemia, and hypertension) were related to greater CIMT
in young adulthood. Effort to change modifiable
risk factors early in life may retard development of atherosclerosis and the
onset of clinical cardiovascular disease later in life.
High dose simvastatin over 2 years reduced combined
carotid/femoral IMT in more than two thirds of patients. The largest effect was
on the femoral artery. This degree of reduction of IMT. . . “will likely have a
significant clinical impact on the prevention of coronary artery disease”.
Primary care clinicians might easily extrapolate these results to other
patients with high cholesterol levels.
Atherosclerosis is reversible.
8-8 EMERGING RISK FACTORS FOR ATHEROSCLEROTIC
VASCULAR DISEASE.
This critical review highlights 4 emerging risk
predictors: C-reactive protein, Lipoprotein (a), Fibrinogen, and Homocysteine.
“Their optimal
use in routine screening and risk stratification remains to be determined.”
“The explanatory power of the major established cardiovascular risk factors has been
systematically underestimated.” (See
previous abstract.)
Primary
care clinicians and their patients have not even begun to assess, prevent, and
treat the established major, modifiable risk factors. Until we do, I believe we need no more risk factors.
We will, with interest, however, follow
the basic science investigations aimed at determining the best mix of risk
factors on which to base clinical interventions.
Exercise capacity and heart rate responses
were strong, graded, and independent predictors of cardiovascular and all-cause
mortality. Not achieving target heart rate and slow return of the rapid heart
rate induced by exercise toward normal predicted future mortality in younger
women.
ST segment depression, while predictive in
men, had no value in women.
The benefit of exercise testing in
asymptomatic women is in determining their cardiovascular fitness.
Women need more fitness exercise
independent of their weight, blood pressure, or lipid levels.
10-17 THE GREATEST THREAT TO WOMEN’S HEALTH
Heart attacks and stroke kill twice as many women as all
cancers combined. Moreover, contrary to conventional wisdom, women are more
likely to die from cardiovascular disease than men.
Getting women to stop smoking, eat healthily, drink alcohol
only in moderation, lose weight if appropriate, and take regular exercise
involves changing behaviors that are often ingrained from childhood.
More
than half of all deaths and disability from heart disease and stroke can be
prevented.
“Advising women, as well as men, about their risks of
cardiovascular disease should, we urge, be mandatory for all primary care
practitioners.”
This study estimated the effects of
strategies based on different drug classes and on those targeting different BP
goals on the risks of major cardiovascular events and death.
Treatment with any commonly-used regimen reduces the
risk of total major cardiovascular events.
A larger reduction in BP reduces risk of total
cardiovascular events. BP-lowering is a major component of the benefit
conferred by the regimens investigated.
There was a larger reduction in stroke and total major cardiovascular
events from regimens aimed at a lower BP goal.
ACE-inhibitor-based regimens benefit across a wide
range of hypertensive and non-hypertensive patients
who
are at high risk for cardiovascular disease.
ACE inhibitor or diuretic or beta-blocker are much
more effective in preventing heart failure than calcium antagonists.
For stroke, there is a greater effect of regimens
based on calcium antagonists than those based on
diuretics or beta-blockers, but the results were of
borderline significance.
Reductions in systolic BP of 2, 4, 6, 8, and 10 mmHg
were associated with lower risk of stroke, major
cardiovascular
disease, coronary heart disease, cardiovascular death, and total mortality.
11-10 END-OF-LIFE CARE AND THE EFFECTS OF
BEREAVEMENT ON FAMILY CAREGIVERS OF PERSONS WITH DEMENTIA
Caregivers in this study showed remarkable resilience in
adapting to the death of their relatives. A large
majority
reported feeling relieved by the death, although persons whose relatives were
institutionalized did not show as rapid a recovery from depressive symptoms.
This suggests that relief from providing daily care did not alone account for
the caregivers’ recovery from bereavement.
Investments in resources for intervention and support
may have the largest benefit when they are
applied
to caregivers and patients in the period immediately preceding the patient’s
death. When caregivers know that their relative is on a trajectory toward
death, and when they are aware of the patient’s disability and suffering, they grieve for the loss of the patient
before the death.
Clinicians should view bereavement not only as a
phenomenon that affects caregivers after the death, but
also
as one that affects many caregivers before the death occurs.
2-6 ADDING A TEST FOR HUMAN PAPILLOMA VIRUS DNA
TO CERVICAL-CANCER SCREENING
Virtually all squamous-cell cervical
carcinomas contain one of eighteen types of human papilloma virus (HPV). The relative risk of cervical cancer
associated with persistent infection with high-risk types of HPV (especially
types 16 and 18) is higher than the risk of lung cancer associated with
smoking.
The discovery that continued presence of
tumor-producing HPV is necessary for development of cervical cancer is
revolutionizing our approaches to screening and prevention. An obvious corrrelary
is that the absence of infection means that the risk of cervical cancer is
negligible.
Compared with annual screening, screening
performed once three years after the last negative test in women who previously
had 3 or more consecutive negative PAP tests, is associated with an average
excess risk of cervical cancer of approximately 3 in 100 000. If continued, screening
annually after 3 negative tests, would result in thousands and thousands of
additional PAP tests and colposcopic examinations to detect only one additional
case of cervical cancer.
The US Preventive Services Task Force
recently recommended screening be performed “at least every 3 years” rather
than every year. The American Cancer Society suggests lengthening the intervals
between screenings to as long as 3 years among women age 30 and over who
previously have had negative results on three or more consecutive cervical
cancer tests.
Given that half of all cases of cervical
cancer occur in women who have never been screened, screening all women at
least once would be expected to contribute more to decreasing mortality than
the continued annual testing. The focus should be on screening women who have
rarely or never undergone screening.
3- 17 APOLIPOPROTEINS VERSUS LIPIDS AS INDICES OF
CORONARY RISK AND AS TARGETS FOR STATIN TREATMENT.
Apo-lipo-protein B (APO-B) is a measure of the total number of atherogenic particles.
APO-B is a risk factor, as is
LDL-cholesterol. The higher the
ABO-B, the higher the risk. In
contrast, APO-A1 is a protective factor, as is HDL-c. The higher
the APO-A1, the lower the risk. Many studies show that APO-B is a better
marker of risk of vascular disease and a better guide to the adequacy of statin
treatment than any cholesterol index.
We are still pursuing the search for the
best, most accurate, most reproducible, least costly risk factor for
cardiovascular disease. LDL-cholesterol
remains the choice at present. Other candidates are forthcoming,
including C-reactive protein and APO-B. It will be interesting to follow the
search. RTJ
In absolute terms, benefits were small, with absolute
differences between groups of 0.6% to 2.1%.
(NNT [to benefit one patient over 3 years] = 47 to 166.)
“Reaction to the 36% relative reduction in the primary
endpoint and the other benefits observed in ASCOT
may
need to be tempered by consideration of the absolute risk reduction of a coronary
event of 3.4 per 1000 patients-years.”
“There are clearly financial implications.” (As well as adverse events from the drug. RTJ)
6-3 HEART PROTECTION STUDY OF
CHOLESTEROL-LOWERING SIMVASTATIN IN 5963 PEOPLE WITH DIABETES
Cholesterol-lowering therapy is beneficial for people
with diabetes even if they do not already have manifest coronary disease or
high cholesterol concentrations. Simvastatin reduced the rate of first major
vascular events by about a quarter in a wide range of diabetic patients.
Treatment over 5-years could prevent about 5 events per 100 persons treated,
High dose simvastatin over 2 years reduced combined
carotid/femoral IMT in more than two thirds of patients. The largest effect was
on the femoral artery. This degree of reduction of IMT. . . “will likely have a
significant clinical impact on the prevention of coronary artery disease”.
Primary care clinicians might easily extrapolate these
results to other patients with high cholesterol levels.
Atherosclerosis is reversible.
9-4 LIFETIME RISK OF CORONARY HEART DISEASE BY
CHOLESTEROL LEVELS AT SELECTED AGES.
For persons of all ages, lifetime risk of CHD increases as total cholesterol
levels rise from under 200 to over 240.
This
supports the important role of cholesterol screening at all ages.
This article is of considerable clinical
importance even though it provided no outcomes from lifestyle or drug interventions. Patients, old and young, now have a reasonable prediction of
lifetime risk according to total cholesterol levels. (And cholesterol
subfractions.) Old, and young should be
screened periodically. The data may convince some younger persons to intervene
to reduce their lifetime risk.
Guidelines suggest lipid screening begin at age 20.
10-8 TAKING SIMVASTATIN IN THE MORNING COMPARED
WITH EVENING
The statin drug, simvastatin, taken in the evening produced
lower cholesterol levels. Lowering LDL-c by 10 mg/dL is clinically significant.
This is achieved with no additional cost or inconvenience
CHRONIC OBSTRUCTIVE PULMONARY
DISEASE (COPD)
2-7 COMBINED SALMETEROL AND FLUTICASONE IN THE
TREATMENT OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE
Combined inhaled long-acting beta
agonist/corticosteroid produced better control of symptoms and lung function
than the use of either component alone, with no greater risk of adverse
effects.
“This combination treatment should be
considered for patients with COPD.”
9-16 METHYLXANTHINES FOR EXACERBATIONS OF CHRONIC
OBSTRUCTIVE PULMONARY DISEASE
When given in conjunction with other standard
treatments, methylxanthines did not confer statistically significant benefits
for lung function, clinical outcomes, and symptoms in patients with
exacerbations of COPD. They
significantly increase nausea and vomiting.
12-10 SCREENING VIRTUAL COLONOSCOPY—READY FOR
PRIME TIME?
A new virtual colonoscopy (VC) used a
multidirectional CT scanner providing a primary
3-dimentional
endoluminal display. It permitted
faster, higher-resolution imaging than previously obtainable. Residual fluid
and stool was tagged by contrast material. The imaging software digitally
removed all opacified fluid and stool from the colon by a process called
“electronic cleansing”.
The study subjects received the VC
followed by conventional colonoscopy for comparison:
Sensitivity of VC for detection of
adenomas vs traditional colonoscopy:
10 mm or larger was 92% vs 88%
8 mm or larger was 92% vs 89%
6 mm or larger was 86% vs 90%
The study suggests that VC can detect
polyps of 6 mm or larger as accurately as conventional colonoscopy in a
population with a low prevalence of colorectal neoplasia.
Decisions regarding the use of VC as a
first-line screening test will require more information about cost and
insurance coverage. “The performance of VC in this asymptomatic population is
impressive, with detection rates similar to those achieved by conventional
colonoscopy.” Only if the important questions about the appropriate size
threshold and the surveillance of smaller polyps can be resolved will VC be
ready for prime time.
The bugaboo is the need for follow-up conventional colonoscopy to
remove suspicious polyps.
Patients will be asking about this. Application in the local community
is likely to be far-off.
Compared with placebo, a daily dose of 325 mg aspirin
reduced risk of adenoma development in patients with a history of surgery for
CRC. (High risk patients.)
3-12 A RANDOMIZED TRIAL OF ASPIRIN TO PREVENT
COLORECTAL ADENOMAS
Low-dose aspirin had a moderate chemoprotective effect
on adenoma formation.
5-10 DIETARY
FIBRE AND COLORECTAL ADENOMA IN COLORECTAL CANCER EARLY DETECTION PROGRAMME
Dietary
fiber from grains, cereals and fruits was associated with decreased risk of
distal colon and sigmoid adenomas.
Compared with placebo, a daily dose of 325 mg aspirin
reduced risk of adenoma development in patients with a history of surgery for
CRC. (High risk patients.)
3-13 ASPIRIN AND PREVENTION OF COLORECTAL CANCER
Among persons with a history of adenomas or CRC the
number of recurrences of adenomas prevented by aspirin (secondary prevention) would be higher than the number of episodes
of bleeding. However, the cumulative clinical importance of bleeding probably
exceeds that of surrogate neoplasm-related outcomes, especially when the effect
of colonoscopic surveillance is taken into account.
If aspirin is used for primary prevention of CRC, it would have
to be given for 10 to 20 years, the time it takes for CRC to develop. The
cumulative adverse effects of aspirin over this time outweigh any benefit in
prevention of CRC, particularly when prevention by screening for CRC is
considered. Long-term use of aspirin for primary prevention of CRC is not
cost-effective. It does not obviate the
need for screening and surveillance.
Aspirin does reduce risk of recurrent
colorectal neoplasia. Whether aspirin has a role in preventing colorectal
cancer and whether it can be used to decrease the required frequency of
screening or surveillance must await results of clinical trials.
4-2 COLON CANCER SCREENING GUIDELINES
The rationale for offering several choices for
screening, which vary widely in their efficacy and cost, is the hope of getting
patients and physicians to consider an initial test. “We wanted to present options so physicians and patients can find
something mutually agreeable, and increase the screening rate.” “You get the biggest bang for the buck from
that initial screen.”
4-3 SCREENING MEN FOR PROSTATE AND COLORECTAL
CANCER IN THE UNITED STATES.
Among
men in the USA, PC screening is more common than CRC screening. Men who choose
to be screened should be made aware of the known mortality benefit of CRC
screening, and the uncertain benefits of screening for prostate cancer.
Men who
insist on PSA screening should be informed of the greater benefit of
colonoscopy.
5-10 DIETARY
FIBRE AND COLORECTAL ADENOMA IN COLORECTAL CANCER EARLY DETECTION PROGRAMME
Dietary
fiber from grains, cereals and fruits was associated with decreased risk of
distal colon and sigmoid adenomas.
12-10 SCREENING VIRTUAL COLONOSCOPY—READY FOR PRIME
TIME?
A new virtual colonoscopy (VC) used a
multidirectional CT scanner providing a primary
3-dimentional
endoluminal display. It permitted
faster, higher-resolution imaging than previously obtainable. Residual fluid
and stool was tagged by contrast material. The imaging software digitally
removed all opacified fluid and stool from the colon by a process called
“electronic cleansing”.
The study subjects received the VC
followed by conventional colonoscopy for comparison:
Sensitivity of VC for detection of
adenomas vs traditional colonoscopy:
10 mm or larger was 92% vs 88%
8 mm or larger was 92% vs 89%
6 mm or larger was 86% vs 90%
The study suggests that VC can detect
polyps of 6 mm or larger as accurately as conventional colonoscopy in a
population with a low prevalence of colorectal neoplasia.
Decisions regarding the use of VC as a
first-line screening test will require more information about cost and
insurance coverage. “The performance of VC in this asymptomatic population is
impressive, with detection rates similar to those achieved by conventional
colonoscopy.” Only if the important questions about the appropriate size
threshold and the surveillance of smaller polyps can be resolved will VC be
ready for prime time.
The bugaboo is the need for follow-up conventional colonoscopy to
remove suspicious polyps.
Patients will be asking about this. Application in the local community
is likely to be far-off.
1-11 PRESCRIBING ORAL CONTRACEPTIVES FOR WOMEN
OLDER THAN 35 YEARS OF AGE.
OC can be safely prescribed to many
women over age 35.
There are many risks and absolute
contraindications. Primary care clinicians should review risks before
prescribing.
10-10 COMBINATION ESTROGEN-PROGESTIN ORAL
CONTRACEPTIVES.
The substantial benefits of O-Cs include avoidance of the
dangers of pregnancy as well as a reduction in risk of ovarian cancer, acne,
dysfunctional uterine bleeding, and possibly endometrial cancer.
Risks include venous thromboembolism and arterial vascular
disease (myocardial infarction and stroke). The challenge for clinicians is to
identify women in whom the risks outweigh the benefits. Both the American
College of Obstetricians and Gynecologists and the WHO have published
guidelines which differ only slightly. (See
abstract)
At
present, the doses of estrogen contained in O-Cs are 2 to 5 times less and the
progestin content is 5 to 10 times less than originally formulated. This reduces
the risk of venous thrombosis without any loss of effectiveness.
“Even
when the health risks are taken into account, the net health benefit of
oral-contraceptive use is great, especially given the effect on risk of ovarian cancer and effectiveness in
preventing pregnancy.”
Hypertension and smoking are the most
common contraindications to be considered.
1-13 ROLE OF DRINKING PATTERN AND TYPE OF ALCOHOL
CONSUMED IN CORONARY HEART DISEASE IN MEN
Among men, consumption of alcohol at
least 3 to 4 times per week reduced risk of MI. Neither the type of beverage, nor the proportion consumed with
meals substantially altered the association.
Men who increased their alcohol
consumption by a moderate amount during the follow-up had a decreased risk of
MI.
1-15 DRUG
ELUTING STENTS IN VASCULAR INTERVENTION
Immunosuppressive agents (which inhibit
tumor-cell growth) may also inhibit the benign tissue proliferation
characterizing intimal hyperplasia. Several immunosuppressants have been tested
for potential to inhibit restenosis. Stents coated with the agents are becoming
available. Local drug delivery achieves higher tissue concentrations of drugs,
while producing no systemic effects. This is associated with a marked reduction
in the risk of re-stenosis.
“The
clinical impact of the elimination of restenosis may influence the approach to
coronary artery disease, the future of cardiac surgery, and health-care
economics.”
2-5 EFFECT OF
IBUPROFEN ON CARDIOPROTECTIVE EFFECT OF ASPIRIN
Ibuprofen negates the protective effect
of low dose aspirin. Use another NSAID.
After one year, there was no difference in
quality-of-life between optimized medical therapy vs early invasive therapy.
However, about half of the medical group needed hospitalization and later
revascularization during the year. Death and non-fatal MI occurred at similar
rates.
Elderly patients with severe angina have
a difficult choice.
3- 17 APOLIPOPROTEINS VERSUS LIPIDS AS INDICES OF
CORONARY RISK AND AS TARGETS FOR STATIN TREATMENT.
Apo-lipo-protein B (APO-B) is a measure of the total number of atherogenic particles.
APO-B is a risk factor, as is
LDL-cholesterol. The higher the
ABO-B, the higher the risk. In
contrast, APO-A1 is a protective factor, as is HDL-c. The higher
the APO-A1, the lower the risk. Many studies show that APO-B is a better
marker of risk of vascular disease and a better guide to the adequacy of statin
treatment than any cholesterol index.
We are still pursuing the search for the
best, most accurate, most reproducible, least costly risk factor for
cardiovascular disease. LDL-cholesterol
remains the choice at present. Other candidates are forthcoming,
including C-reactive protein and APO-B. It will be interesting to follow the
search. RTJ
In absolute terms, benefits were small, with absolute
differences between groups of 0.6% to 2.1%.
(NNT [to benefit one patient over 3 years] = 47 to 166.)
“Reaction to the 36% relative reduction in the primary
endpoint and the other benefits observed in ASCOT
may
need to be tempered by consideration of the absolute risk reduction of a
coronary event of 3.4 per 1000 patients-years.” “There are clearly financial implications.” (As well as adverse events from the drug. RTJ)
7-4 MORTALITY RISK REDUCTION ASSOCIATED WITH
SMOKING CESSATION IN PATIENTS WITH CORONARY DISEASE.
Smoking cessation has a greater effect on reducing the risk of
mortality among patients who smoke than the effect of any other intervention.
Risk of death was reduced by 36% in
those who quit.
Ask your patients who smoke to read this article.
8-2 ESTROGEN PLUS PROGESTIN AND THE RISK OF
CORONARY HEART DISEASE.
E-P, in standard dose, does not confer cardiac
protection. It may slightly increase risk of CHD, especially during the first
year of use. Primary care clinicians may consider prescribing low-dose aspirin
for primary prevention, at least during the first year. Treatment to improve
lipid profiles reduces risk.
E-P should not be prescribed for the prevention of
cardiovascular disease.
Any possible increase in incidence of CHD (about 6
extra cases per 10 000 patient-years) is minor compared with the risk for
breast cancer.
8-7 PREVALENCE OF CONVENTIONAL RISK FACTORS IN
PATIENTS WITH CORONARY HEART DISEASE.
At least 80% to 90% of patients with CHD have
conventional risk factors (cigarette smoking, diabetes, dyslipidemia, and
hypertension). This is probably an
underestimate. Clinical medicine, public health policies, and research efforts
should place significant emphasis on the 4 factors and lifestyle behaviors.
Non-traditional risk factors and genetic causes deserve less emphasis.
“Although widely asserted, the belief that more than
50% of patients with CHD lack conventional risk
factors
is not supported by primary data.” “In essence, patients without conventional
risk factors are unlikely to develop CHD.”
“The true
prevalence of conventional risk factors is certainly higher than identified in
our study.”
Many
patients with hypertension and diabetes are not aware of their condition. More
stringent cutoffs for BP, lipids, and blood glucose have been increasingly
recommended.
“It is
increasingly clear that the 4 conventional risk factors and their resulting
health risks are largely
preventable
by a healthy life-style.”
Primary care clinicians have their hands full
encouraging patients to deal with these conventional risk factors. We don’t
need more at this time.
Among patients with stable CAD without apparent heart failure, the angiotensin converting
enzyme
inhibitor, perindopril (Aceon) improved outcomes. This was in addition to use of other
preventive drugs.
[NNT(4 years to benefit one) = 50]
ACE inhibitors have been shown to have the broadest
impact of any drugs in cardiovascular medicine, reducing the risk of death,
myocardial infarction, stroke, diabetes, and renal impairment. They benefit
patients with heart failure, post myocardial infarction left ventricular
dysfunction, peripheral vascular disease, diabetes, stroke, and transient ischemic
attacks.
As long-term therapy, perindopril is expensive. It has
not been compared with less expensive ACE inhibitors (eg, enalapril) which may
be just as effective.
ACE inhibition
is underused in primary care practice.
9-4 LIFETIME RISK OF CORONARY HEART DISEASE BY
CHOLESTEROL LEVELS AT SELECTED AGES.
For persons of all ages, lifetime risk of CHD increases as total cholesterol
levels rise from under 200 to over 240.
This
supports the important role of cholesterol screening at all ages.
This article is of considerable clinical
importance even though it provided no outcomes from lifestyle or drug interventions. Patients, old and young, now have a reasonable prediction of
lifetime risk according to total cholesterol levels. (And cholesterol
subfractions.) Old, and young should be
screened periodically. The data may convince some younger persons to intervene
to reduce their lifetime risk
Guidelines suggest lipid screening begin at age 20.
In
smokers with CAD who quit, risk of sudden cardiac death (SCD) is significantly reduced and compares with the risk of those who never
smoked. The decline in risk associated with cessation is immediate and not time
dependent. This supports the view that the risk is due to direct toxic effects.
The risk in smokers is not related to the amount of smoking.
In absolute terms, smoking cessation and never smoking
resulted in a 3.5% lower risk of SCD over 8 years
compared
with those who continued to smoke. [NNT(8 years to prevent one SCD) = 30]. And a 11% reduction in all-cause death. [NNT
= 10].
The risk of continuing smoking on SCD is even more
pronounced than other risk factors—age, sex,
New York
Heart Association functional class, BP, and dyslipidemia.
Cessation is certainly one of the most effective preventive
measures. Despite being informed of the risks, many patients continue to smoke.
Primary care clinicians who succeed in getting recalcitrant smokers to stop
achieve a major therapeutic intervention. Would asking them to read a copy of
this article help? RTJ
Perioperative (before and after surgery) use of a
COX-2 inhibitor was effective component of multimodal analgesia. It reduced
opioid consumption, pain, vomiting, and sleep disturbance. It shortened the
time physical therapy was needed to achieve effective joint range of motion.
Pain is the 5th monitored vital sign.
Efficient management of pain improves postoperative clinical outcomes. After
total knee arthroplasty (TKA), inadequate control of postoperative pain is
associated with poor functional recovery.
Surgical trauma induces cyclo-oxygenase
2 (COX-2) which then promotes
synthesis of prostaglandins that sensitize peripheral nocioceptors and mediate
central sensitization. NSAIDs as well as opioids decrease this inflammatory
response. Pre-operative
administration of NSAIDs may be effective by establishing a sufficient tissue
NSAID concentration to inhibit early production of prostaglandins before the
onset of tissue trauma, thus attenuating the development of hyperalgesia.
I wonder if sports medicine enthusiasts
might offer pre-game COX-2 inhibitors to players (eg, football) who might be
subject to injury during a game. This might lessen the period of disability if
a serious injury should occur.
2-12 PANEL ENDORSES LIMITED ROLE FOR CRP TESTS
C-reactive protein (CRP) has emerged as
the leading inflammatory marker for cardiovascular disease.
Does the test add anything to the list
of risk markers now available? How
should it be used?
A
guideline suggests that CRP has its greatest utility in people deemed at
intermediate risk of CVD. (intermediate risk = 10% to 20% risk of developing
CVD in the next 10 years as calculated from the Framingham risk score.) Physicians should assess traditional risk
factors and calculate the absolute Framingham risk score before testing with CRP.
http://hin.nhlbi.nih.gov/atpiii/calculator.asp?usertype=prof
CRP should not be used routinely, or as an alternative
to traditional risk factor assessment.
It is not known if an elevated CRP as the sole risk marker needs
treatment.
7-8 NURSES’ EXPERIENCES WITH HOSPICE PATIENTS
WHO REFUSE FOOD AND FLUIDS TO HASTEN DEATH.
Voluntary refusal of food and fluids has been proposed
as an alternative to physician-assisted suicide (PAS) for terminally ill patients who wish to hasten death. Oregon
hospice nurses reported the quality of the process of dying for most of these
patients was good.
But, “We don’t know enough about it.” “We have to get this out and talk about it,
because this is happening.”
Best evidence indicates that antibiotics
are of minimal or no benefit for sore throat, acute bronchitis, the common
cold, and otitis media. Antibiotics continue to be commonly used for these
conditions. This is potentially
inappropriate prescribing.
This has prompted the use of delayed (or
“as needed”, or “if”) prescriptions. These prescriptions
are
written with the proviso that they are not to be used immediately—only later if
symptoms do not improve in a few days. Use of a delayed prescription should be
restricted to patients who request antibiotics or for whom the doctor thinks
one is not immediately indicated.
A randomized trial in 1997 gave
prescriptions for antibiotics for respiratory infections: 1) to be filled
immediately, or 2) to be filled after 3 days, or 3) no antibiotic prescription.
The immediate group filled 99%.
The delayed group filled 31%.
In the no-prescription group,
13% filled an antibiotic prescription after a return visit to
the physician.
The reduction in use of antibiotics for
upper respiratory infections through using delayed prescriptions is as
effective, and in many cases, more effective than educational projects.
3-5 SILENT BRAIN INFARCTS AND THE RISK OF
DEMENTIA AND COGNITIVE DECLINE
Silent brain infarcts are common in the
elderly. Persons with silent brain infarcts had an increased risk of dementia,
and a steeper decline in cognitive function than persons without such lesions.
In clinical practice—How can we intervene to benefit
the patient? The hope is that treatment directed at vascular disease will
reduce the burden of dementia. We should optimize cardiovascular health by
established means: control of hypertension; lipid control; weight control; exercise;
smoking-avoidance.
Other possible beneficial interventions: low-dose
aspirin; one alcoholic drink
daily; and folic acid supplementation
to reduce homocysteine levels.
4-5 PROSPECTIVE STUDY OF ALCOHOL CONSUMPTION AND
RISK OF DEMENTIA IN OLDER ADULTS
Compared with abstinence, consumption of 1 to 6 drinks weekly was
associated with a lower risk of dementia among older adults.
Estrogen
+ progestin did not reduce the risk for probable dementia in postmenopausal
women age 65 and older.
6-15 LEISURE ACTIVITIES AND THE RISK OF DEMENTIA
IN THE ELDERLY
Participation in leisure-time mental activities was
associated with reduced risk of dementia and rate of decline in memory.
Frequent participation in leisure-cognitive activities
was associated with a reduced risk of dementia over an ensuing 5 years. The
activities include playing board games, reading, playing musical instruments,
and doing crossword puzzles. The brain has use-dependent plasticity. Effortful
mental activity may not only strengthen existing connection, but stimulate
neurogenesis. Persistent engagement by the elderly in effortful mental
activities may promote plastic changes in the brain that circumvent the
pathology underlying the dementia.
A growing proportion of the approximately 4 million
older US adults with Alzheimer’s disease or other dementias are surviving to
the advanced stages of their disease.
Eating and swallowing problems typically develop during the terminal
stages. Whether to initiate feeding tube use or to focus on comfort care is a
challenging dilemma facing families, clinicians and institutions.
Growing empirical data and expert opinion indicates that feeding tubes
has no demonstrable health benefits in this population, and may be associated
with increased risks and discomfort.
The quality of care of cognitively
impaired patients in nursing homes is inversely related to the numbers who have
feeding tubes in place.
“Comprehensive implementation of advanced care planning
is likely to reduce the use of feeding tubes.”
11-10 END-OF-LIFE CARE AND THE EFFECTS OF
BEREAVEMENT ON FAMILY CAREGIVERS OF PERSONS WITH DEMENTIA
Caregivers in this study showed remarkable resilience
in adapting to the death of their relatives. A large
majority
reported feeling relieved by the death, although persons whose relatives were
institutionalized did not show as rapid a recovery from depressive symptoms.
This suggests that relief from providing daily care did not alone account for
the caregivers’ recovery from bereavement.
Investments in resources for intervention and support
may have the largest benefit when they are
applied
to caregivers and patients in the period immediately preceding the patient’s
death. When caregivers know that their relative is on a trajectory toward
death, and when they are aware of the patient’s disability and suffering, they grieve for the loss of the patient
before the death.
Clinicians should view bereavement not only as a
phenomenon that affects caregivers after the death, but
also
as one that affects many caregivers before the death occurs.
11-11 DEMENTIA WITH LEWY BODIES
Dementia with Lewy bodies (DLB) is one of the 3 most common causes of dementia in older
people. Alzheimer’s disease and vascular dementia are the other two.
The clinical presentation of DLB
typically includes: fluctuating
cognitive impairment, visuospatial dysfunction, marked attention deficits,
psychiatric symptoms (especially complex visual hallucinations), and mild
extrapyramidal features. DLB can usually be differentiated from Parkinson’s
disease with dementia because in DLB the motor symptoms usually develop after the cognitive impairment. Some authorities require, as a diagnostic
criterion for Parkinson’s disease, a delay of at least 12 months between the
onset of motor symptoms and subsequent cognitive impairment.
My dictionary defines Lewy body as an eosinophilic
inclusion body found in the cytoplasm of neurons in the cortex and brain stem
in Parkinson’s disease and some forms of dementia. But, as I understand it, DLB is not a form of Parkinsonism,
although when dementia occurs in Parkinsonism, the two may be confused. The pathology differs.
There is a “need to maintain a high
degree of awareness of DLB especially when prescribing neuroleptic drugs for
people whose dementia is characterized by early psychiatric symptoms.”
Neuroleptic drugs (more simply anti-psychotic drugs) include phenothiazines.
(eg, chlorpromazine [Thorazine],
thioridazine, perphenazine, fluphenazine).
Severe neuroleptic sensitivity reactions may occur.
DLB may respond to cholinesterase
inhibitors.
I abstracted this short article to learn more about Lewy
dementia. I had not understood much about it.
Still, making the diagnosis does not
help the patients much.
6-16
AWARENESS ABOUT DEPRESSION: Important for All Physicians
A nationally representative household survey of the 48
contiguous United States found that the lifetime prevalence of major
depression is 16%. Recognition and
treatment of depression in primary care practice is woefully inadequate.
Screening is indicated in primary care
practice.
A helpful website is cited.
12-7 SCREENING FOR DEPRESSION IN PRIMARY CARE
WITH TWO VERBALLY ASKED QUESTIONS
The US Preventive Services Task Force endorsed
screening for depression, but did not recommend a specific tool. Many primary
care clinicians find screening questionnaires for depression too cumbersome and
time consuming for routine use.
This study used a simple screening tool of two
questions. If one or two were answered positively, the screen was considered
positive, and further questions were asked to determine if major depression was
present. (A composite interview--the “Gold Standard”)
The screening questions:
1) During the past month have you often been bothered by feeling
down, depressed, or hopeless?
2) During the past month have
you often been bothered by little interest or pleasure in doing things?
In the community setting, the two
verbally asked questions have a good sensitivity (97%)
and
reasonable specificity (67%) for screening for depression. If the screen was
negative (both questions answered negatively) major depression is almost surely
absent.
About 5 false positives would occur for
every true positive when asking the questions alone.
This is common in screening studies
which are in essence a diagnostic test performed in a low prevalence setting.
Further questions will be required to clarify presence or absence of
depression.
1-3 MULTIFACTORIAL INTERVENTION AND
CARDIOVASCULAR DISEASE IN PATIENTS WITH TYPE 2 DIABETES
A targeted long-term intensive
intervention aimed at multiple risk factors (hypertension, dyslipidemia,
microalbuminuria) in patients with DM-2 and microalbuminuria reduced the risk
of cardiovascular and microvascular events by about 50%.
1-4 GLYCEMIC
EFECTS OF POSTMENOPAUSAL HORMONE THERAPY
In women with established coronary heart
disease, hormone therapy reduced the incidence of type 2 diabetes by 3.3%
compared with those taking placebo. NNT (4 years to prevent one case) = 30.
And reduced incidence of diabetes by 12%
in those with impaired glucose tolerance at baseline.
4-12
EFFECT OF MULTIVITAMIN AND MINERAL SUPPLEMENT ON INFECTION AND QUALITY OF LIFE
A daily multivitamin-mineral supplement was associated
with reduced incidence of patient-reported infection and related absenteeism in
the subset of patients with type 2 diabetes who had a high prevalence of
subclinical micronutrient deficiency.
5-3 USING NEW
INSULIN STRATEGIES IN THE OUTPATIENT TREATMENT OF DIABETES.
One daily
injection of insulin glargine along with mealtime injections of insulin lispro
significantly improves glycemic control in patients with poorly controlled type
2 DM. The combination matches each patient’s needs, simplifies adjustment of
dose, and improves control while causing fewer episodes of hypoglycemia. “They
are easier to use than many patients and clinicians realize.”
6-3 HEART PROTECTION STUDY OF
CHOLESTEROL-LOWERING SIMVASTATIN IN 5963 PEOPLE WITH DIABETES
Cholesterol-lowering therapy is beneficial for people
with diabetes even if they do not already have manifest coronary disease or
high cholesterol concentrations. Simvastatin reduced the rate of first major
vascular events by about a quarter in a wide range of diabetic patients.
Treatment over 5-years could prevent about 5 events per 100 persons treated,
6-5 RELATIONSHIP OF WALKING TO MORTALITY AMONG
US ADULTS WITH DIABETES
Regular walking is likely to increase longevity across
a diverse spectrum of adults with diabetes. Successful efforts to increase
physical activity in the diabetic population could have broad public health
benefits.
6-6 WALKING, THE BEST MEDICINE FOR DIABETES?
“Walking is probably the ‘best medicine’ for both
prevention and treatment of diabetes mellitus.”
6-7 INTENSIVE DIABETES THERAPY AND CAROTID
INTIMA-MEDIA THICKNESS IN TYPE 1 DIABETES MELLITUS
Intensive therapy over an extended time
resulting in a mean HbA1c of 7.2% decreased progression of intima-media
thickness. Evidence that tight control may delay macro-vascular disease.
6-13 REGRESSION OF MICROALBUMINURIA IN TYPE 1
DIABETES.
Urinary albumin excretion does not imply inexorable
progression of diabetic nephropathy. Regression frequently occurs, associated
with lower HbA1c levels, lower BP, and lower levels of cholesterol and
triglycerides.
8-15 POOR GLYCEMIC CONTROL CAUSED BY INSULIN
INDUCED LIPOHYPERTROPHY.
Prevalence of lipohypertrophy in patients with type 1
diabetes is estimated to be around 20% to 30%. It is due to a cellular response
of adipocytes to the local effects of injected insulin. Immunological factors
may be important. Frequent injection into the same site is related to
incidence.
Injection repeatedly given into these
sites may lead to problems of glycemic control. Insulin absorption can be significantly delayed.
The development of decreasing glomerular filtration rate
and end-stage renal disease is a long pathological process presumably
reflecting the effects of hyperglycemia on renal cells.
The Diabetes Control and Complications Trial (DCCT; 1993)
demonstrated the benefits of intensive treatment of diabetes over 6.5 years in
reducing glycemic levels and slowing the progression of diabetic nephropathy.
The present study followed the DCCT cohort for an additional 8 years to
determine if the benefits of intensive vs conventional treatments on kidney
function would persist.
Benefits were persistent, reducing incidence of
hypertension and albuminuria for 8 years after the end of the original study
despite deteriorating glucose control.
In addition, there were clear residual
benefits of intensive treatment on future development of hypertension over the
ensuing 8 years.
The intensively treated participants had few manifestations
of nephropathy during the DCCT due to their relatively low level of HbA1c. The
near normal hyperglycemic control for 6.5 years may have simply delayed the
development of indicators of diabetic nephropathy during the 8 more years of
follow-up.
I believe primary care clinicians will
have little difficulty extrapolating these benefits to patients with type 2
diabetes. The greater the number of days with normal glucose levels, the longer
the delay in development of microvascular complications.
10-9 INHALED INSULIN PROVIDES IMPROVED GLYCEMIC
CONTROL IN PATIENTS WITH
TYPE
2 DIABETES MELLITUS INADEQUATELY CONTROLLED WITH ORAL AGENTS.
Recently, a
dry powder inhaled insulin (IN-I) system has been developed. It
provides a new method of treatment. The pulmonary route exploits the large
vascular bed and permeability of the alveoli to deliver insulin directly into
the blood stream. IN-I has a rapid onset of action, actually faster than
injected regular insulin and insulin lispro. Its duration of action is about 6
hours.
Pre-meal inhaled powdered insulin (IN-I) added to oral agents produced
a significantly greater reduction in HbA1c than oral agents alone (metformin or
sulfonylurea, or both)—a mean reduction in HbA1c of 2.3 %. HbA1c remained stable in the control group—about
10%
One third of the IN-I
+ oral agents group achieved a HbA1c less than 7% vs none in the oral
agents alone group. (Mean HbA1c dropped from about 10% to 7.5% in the IN-I
group.)
Fasting plasma glucose improved significantly.
This means of administration will eliminate the fear of
injections. Patient satisfaction was high--97% opted to continue in a 1-year
extension of the therapy.
This is an early proof of concept study.
Primary care clinicians will watch for developments with great interest. Cost
is to be determined.
1-2 ADVERSE EVENTS ASSOCIATED WITH DIETARY
SUPPLEMENTS
“Dietary supplements” are associated with adverse effects that
include all organ systems, age groups, and levels of severity,
Associations between adverse effects and
ingredients are difficult to verify. Information systems are incomplete.
Our strong message should be:”. “You do
not know what you are taking”. “You do not know if it is safe”.
4-7 EFFICACY AND SAFETY OF LOW-CARBOHYDRATE
DIETS
Despite the abundance of lay literature on the topic
of low-carbohydrate (Atkins’) diets, marked discordance exists between the
knowledge needed to guide dietary choices and the information that is available
in the medical literature.
There is insufficient evidence to make
recommendations for or against the use of low-carbohydrate diets. Among the
published studies, participant weight loss while using low-carbohydrate diet
was principally associated with decreased caloric intake and increased
duration, but not with reduced carbohydrate content.
4-8 LOW-CARBOHYDRATE DIETS AND REALITIES OF
WEIGHT LOSS
“Without carbohydrate-containing foods (eg, breads)
less fat is ingested because few people eat much fat by itself.” Thus, low-carbohydrate diets reduce calorie
intake.
A potential advantage of very
low-carbohydrate diets is that removing sweets from the diet can reduce the
gustatory stimulation that sweets produce. (This gustatory stimulation by
sweets easily leads to over consumption.)
The low-carbohydrate diets do reduce consumption of
high fructose soft drinks, but do not deal with the preference that many humans
have for sweets. “The aspect of carbohydrates as a preference in the diet is
one that still needs to be addressed.”
The broader issue of whether a unique diet exists that
will produce long-term weight loss has yet to be evaluated. That “a calorie is
a calorie” has been reaffirmed. The question of whether patients can adhere
more easily to one type of diet or other remains to be answered.
6-4 ADHERENCE TO A MEDITERRANEAN DIET AND
SURVIVAL IN A GREEK POPULATION
The traditional Mediterranean diet (MD) is characterized by a high intake
of vegetables, legumes, fruits, nuts, and cereals (largely unrefined). Also a
high intake of olive oil (the principal source of fat), a low intake of
saturated fats, and a moderately high intake of fish. Dairy products are mostly
in the form of cheese and yogurt. Intake of meat and poultry is
low-to-moderate. Wine is often taken with meals.
Greater adherence to the diet was associated with a
significant reduction in mortality.
5-2 WHAT DO
DOCTORS FIND MEANINGFUL ABOUT THEIR WORK?
Making a
difference in someone else’s life was the most common theme in the doctors’
stories. It was not making a brilliant diagnosis or an adroit technical
intervention. Most of these stories took place in the context of chronic,
incurable conditions, or end-of-life care. The doctors felt awed and deeply
rewarded that their mere presence could be healing and comforting to patients.
12-9 EFFICACY AND SAFETY OF ECHINACEA IN
TREATING UPPER RESPIRATORY TRACT INFECTIONS IN CHILDREN
Echinacea is a herbal remedy widely used
for prevention and treatment of upper respiratory infections (URIs). It is one of the most commonly
used herbal remedies in the USA . Three species of echinacea are used.
Beneficial effects are thought to be due to its “immunomodulating” activity,
most notably macrophage activation and enhanced neutrophil phagocytosis.
This study postulated that treatment with E purpurea would result in at least a
1.5- to 2-day reduction in duration of URIs in children, and that symptoms
would be less severe than in patients receiving placebo.
The preparation used in this study was not effective in treating URIs in
children. After the trial was completed, parents could not guess correctly whether their child had taken echinacea or
placebo. “Our results do not support
the use of echinacea for treatment of URIs in children.” Its use was associated with an increased
risk of rash.
This study was supported by a grant from
the National Center for Complementary and Alternative Medicine, Bastyr
University (an alternative medicine institution) and National College of
Naturopathic Medicine, Portland Oregon.
It
continues to amaze me that so many persons take unstandardized and unproven
nostrums and give them to their children. I am sure devotees will fault this
study. They will remain convinced that echinacea is beneficial.
Progestin alone has been approved by the FDA for
emergency contraception (EC)—a total
of 1.5 mg of levonorgestrel—two 0.75 mg tablets to be taken 12 hours apart (Plan B). (Both tablets can be taken
at once without loss of efficacy.)
Pregnancy rates are lowest when EC is used within 12
hours of unprotected intercourse. Most studies report a monotonic decrement in
effectiveness as the interval increases. Two studies have indicated that EC
given within 5 days is still effective.
“Emergency contraception should thus be offered for any act of
unprotected intercourse that has occurred in the preceding 5 days.” Because the
day of ovulation in generally unknown, even in women who report regular cycles,
treatment is indicated regardless of the cycle day on which unprotected
intercourse occurred.
There are no absolute contraindications. Even in women
who have contraindications to long-term
use
of birth control pills, the balance of risks and benefits favors the brief
exposure of EC over the risks of pregnancy. Ectopic pregnancy has been
reported, but there is no good evidence of increased risk.
The FDA is currently evaluating an application for
over-the-counter status for the levonorgestrel-only formulation. It is highly
suitable for such a switch. The dose is
the same for everyone; no contraindications to use; adverse events are rare; no
potential for addiction; repeated use is safe and reasonably effective. Use is
highly acceptable to patients and is associated with high rates of continuation
of oral contraceptives.
11-10 END-OF-LIFE CARE AND THE EFFECTS OF
BEREAVEMENT ON FAMILY CAREGIVERS OF PERSONS WITH DEMENTIA
Caregivers in this study showed remarkable resilience
in adapting to the death of their relatives. A large
majority
reported feeling relieved by the death, although persons whose relatives were
institutionalized did not show as rapid a recovery from depressive symptoms.
This suggests that relief from providing daily care did not alone account for
the caregivers’ recovery from bereavement.
Investments in resources for intervention and support
may have the largest benefit when they are
applied
to caregivers and patients in the period immediately preceding the patient’s
death. When caregivers know that their relative is on a trajectory toward
death, and when they are aware of the patient’s disability and suffering, they grieve for the loss of the patient
before the death.
Clinicians should view bereavement not only as a
phenomenon that affects caregivers after the death, but
also
as one that affects many caregivers before the death occurs.
8-3 IS OPPORTUNISTIC DISEASE PREVENTION IN THE
CONSULTATION ETHICALLY JUSTIFIABLE?
Consultations in primary health care
have been suggested as an ideal setting for health promotion and disease
prevention. Doctors are expected to discuss preventive measures even when they
are not among the reasons for the consultation. Opportunistic preventive
medicine is considered a part of good medical practice. This article asks. .
.Is this ethically justifiable?
The authors argue that doctors should
maintain a clear focus on each patient’s reasons for seeking help rather than
be distracted by an increasing list of preventive measures. They maintain that,
from a moral point of view, initiatives to improve health among people who are
currently free of symptoms is fundamentally different from curative
medicine—the condition for which the patient consults.
Physicians who offer a screening test carry a
considerable responsibility. They must offer enough information about risks and
benefits in order to enable the patient to give informed consent. Informed consent presupposes an understanding
of the limitations of the screening test. Every test carries a chance of
misclassification of disease. A false positive test may result in further
interventions that do not benefit the patient, and may cause harm.
“Once medical risk has been passed on to a person, it
cannot be retracted. Respect for autonomy should therefore also honor the
person’s right not to be
opportunistically confronted with knowledge about biomedical risks that are
unrelated to his or her reasons for seeing the doctor.”
“As the list of accessible preventive tests lengthens
and thresholds for intervention are lowered, a doctor who adheres to all
recommendations for provision of preventive services may ultimately be able to
find something abnormal in everybody.”
Think twice before advising screening tests.
12-8 REVIEW
OF SENSITIVITY, SPECIFICITY, PREDICTIVE VALUES AND LIKELIHOOD RATIOS
Calculate sensitivity from the left
column; specificity from the right column; positive predictive value from the
top row; negative prediction value from
the bottom row; the likelihood ratios from both columns.
See text.
Exercise capacity and heart rate responses
were strong, graded, and independent predictors of cardiovascular and all-cause
mortality. Not achieving target heart rate and slow return of the rapid heart
rate induced by exercise toward normal predicted future mortality in younger
women.
ST segment depression, while predictive in
men, had no value in women.
The benefit of exercise testing in asymptomatic
women is in determining their cardiovascular fitness.
Women need more fitness exercise
independent of their weight, blood pressure, or lipid levels.
6-8 NON-ALCOHOLIC FATTY LIVER DISEASE: An Unrecognized Cause Of Cryptogenic
Cirrhosis
Cryptogenic
cirrhosis (CC) is a significant
contributor to liver related morbidity. Non-alcoholic fatty liver disease (NAFLD) is the most common cause of CC.
The diagnosis of cirrhosis in these patients is usually delayed by almost a
decade and is often not established until after the patient develops
hepatocellular carcinoma or other complications of advanced liver disease. Once
cirrhosis is diagnosed, mortality is greater than that of hepatitis C virus
related cirrhosis.
Existing evidence, albeit scant, suggests that NAFLD
is a spectrum, progressing from hepatic steatosis to non-alcoholic
steatohepatitis, and then on to cirrhosis. Over 6 million US adults have NAFLD,
and 640 000 may have cirrhosis. This may exceed the numbers infected with
hepatitis C. Prognosis is just as bad.
Diagnosis remains one that is established only after
other causes of chronic liver disease have been excluded. NAFLD can be more
readily suspected if the patient is obese and has diabetes. Primary care
clinicians have an opportunity for prevention by controlling obesity, lipids,
and diabetes.
A growing proportion of the approximately 4 million
older US adults with Alzheimer’s disease or other dementias are surviving to
the advanced stages of their disease.
Eating and swallowing problems typically develop during the terminal
stages. Whether to initiate feeding tube use or to focus on comfort care is a
challenging dilemma facing families, clinicians and institutions.
Growing empirical data and expert opinion indicates that feeding tubes
have no demonstrable health benefits in this population, and may be associated
with increased risks and discomfort.
The quality of care of cognitively
impaired patients in nursing homes is inversely related to the numbers who have
feeding tubes in place.
“Comprehensive implementation of advanced care
planning is likely to reduce the use of feeding tubes.”
Cereal fiber consumption (equivalent to
2 slices of whole grain bread) in later life was associated with lower risk of
incident CVD.
5-10 DIETARY
FIBRE AND COLORECTAL ADENOMA IN COLORECTAL CANCER EARLY DETECTION PROGRAMME
Dietary
fiber from grains, cereals and fruits was associated with decreased risk of
distal colon and sigmoid adenomas.
PHYSICAL ACTIVITY (SEE ALSO FITNESS)
5-8
RELATIONSHIP OF CHANGES IN PHYSICAL ACTIVITY AND MORTALITY AMONG OLDER
WOMEN
Increasing
and maintaining physical activity levels could lengthen life for older women.
6-5 RELATIONSHIP OF WALKING TO MORTALITY AMONG
US ADULTS WITH DIABETES
Regular walking is likely to increase longevity across
a diverse spectrum of adults with diabetes. Successful efforts to increase
physical activity in the diabetic population could have broad public health
benefits.
6-6 WALKING, THE BEST MEDICINE FOR DIABETES?
“Walking is probably the ‘best medicine’ for both
prevention and treatment of diabetes mellitus.”
Exercise capacity and heart rate responses
were strong, graded, and independent predictors of cardiovascular and all-cause
mortality. Not achieving target heart rate and slow return of the rapid heart
rate induced by exercise toward normal predicted future mortality in younger
women.
ST segment depression, while predictive in
men, had no value in women.
The benefit of exercise testing in
asymptomatic women is in determining their cardiovascular fitness.
Women need more fitness exercise
independent of their weight, blood pressure, or lipid levels.
Once-daily fondaparinux without monitoring is at least as
effective and safe as adjusted-dose IV unfractionated heparin in the initial
treatment of hemodynamically stable patients with pulmonary embolism.
“Because of its simplicity, once-daily
subcutaneous fondaparinux without anticoagulation monitoring could replace
intravenous administration of unfractionated heparin in most patients.”
2-1 ACCURACY OF OTTAWA ANKLE RULES TO EXCLUDE
FRACTURES OF THE ANKLE AND MID-FOOT
1)
Inability to bear weight and walk 4 steps immediately after the injury, or on
presentation to the
emergency
department.
2) Bony tenderness localized to the
posterior edge (and up to 6 cm above) either malleolus
(four
spots).
Fewer
than 2% of patients negative for fracture by the rules actually had fracture.
Application
of the rules greatly reduces the number of X-rays taken.
Vitamin D supplements of 100 000 IU given orally every
4 months for primary prevention was
associated with a lower risk of fractures (and without adverse effects) in
older men and women living in the community.
This is equivalent to our usual dose of 800 IU daily.
Calcium supplements would have lowered risk even more.
3-7 MOVING BEYOND SINGLE AND DUAL DIAGNOSIS IN
GENERAL PRACTICE.
“The awkward phrase ‘multiple morbidity’ describes the
common predicament of the many patients who have more than one health
problem.” Poor health is inextricably
linked to low income, unemployment, poor housing, and inadequate social support
as well as old age.
The trend towards more specialization tends to
disadvantage people with multiple morbidity. The effective management of such
patients depends heavily on primary care practice.
“As general practitioners it is our job
to manage all of a patient’s health problems by drawing on help for specialists
where we can.”
7-3 STRUCTURAL AND SYMPTOMATIC EFFICACY OF
GLUCOSAMINE AND CHONDROITIN IN KNEE OSTEOARTHRITIS
Evidence that glucosamine benefits symptoms and slows
joint deterioration.
The purity and dose of these
over-the-counter preparations are not regulated by the FDA.
Primary care clinicians may be willing
to prescribe it despite regulation by the FDA.
Hyperuricemia is central to gout, but does not inevitably
cause disease. Indeed, urate levels are frequently normal during attacks. Factors other than serum urate contribute to
clinical gout in an additive manner—hypertension, thiazide and loop diuretics,
obesity, and high alcohol intake. Gout is also associated with insulin
resistance.
Lifestyle changes sometimes return uric acid levels to
normal--stop drinking alcohol, switch from thiazides, or, if obese, lose
weight. Conventional low purine diets are unpalatable and typically are only
moderately effective.
Treatment of acute attacks include NSAIDs, corticosteroids,
and colchicine.
Long term prophylactic treatment includes NSAIDs,
colchicine, and allopurinol.
Although most patients have substantially reduced renal
urate clearance (probenecid may used for these patients). . . “It is common and
acceptable practice to use the xanthine oxidase inhibitor allopurinol (Generic; Zyloprim), which inhibits uric
acid synthesis whether or not the patient overproduces urate.” “Irrespective of
the cause of hyperuricemia, allopurinol is the most frequently used
anti-hyperuricemic agent.” Its once-daily administration is convenient and
effective regardless of the cause of the hyperuricemic.
8-13 ENDOCRINE TREATMENT OF PHYSIOLOGICAL
GYNECOMASTIA
“Physiological” gynecomastia is due to an altered
ratio between free estradiol (a stimulant) and testosterone (an inhibitor).
Anti-estrogens such as tamoxifen (Nolvadex)
have therefore been suggested as non-surgical treatment. Various published
studies have used tamoxifen at a dose of 10 to 40 mg daily for several months.
Resolution of the lump and pain has been reported in 80% of cases. Only minor
and reversible side effects were reported.
11-4 STARTING EARLIER TO PREVENT HEART DISEASE.
Two studies reported in the November 5 issue of JAMA measured carotid artery
intima/media thickness (IMT) in young adults (age 24 to 37). LDL-cholesterol
and BMI had been measured in childhood, up to 22 years earlier. Higher
childhood levels of both predicted increased adult carotid IMT. In one study,
systolic BP and smoking in adolescence also predicted increased IMT. (The
higher the carotid IMT, the greater the extent of coronary atherosclerosis.)
It is clear that risk factors begin to matter during
adolescence, the age range during which fatty streaks in the coronary arteries
begin to be converted to raised lesions, and when high-risk populations begin
to diverge from low-risk populations.
“It may be possible that risk factors in the early teen-age years are
associated with permanent damage to the arterial wall.”
Assessing risk factors in youth is easy and
inexpensive. Cholesterol and other risk factors do matter during adolescence.
It may now be time to reconsider the age at which measurement of cholesterol
and life-style changes should begin. The difficulty of changing life styles in
teenagers, however, should not be underestimated. Physicians caring for
children and adolescents should be sure their patients and their parents know
it is beneficial and safe to promote and maintain a healthy life style.
Changing ingrained life-style habits in
teen-agers is almost impossible. Parents must set the example and begin
lifetime habits of their children at a pre-teen age.
2-9 EFFECTS OF INITIATING CARVEDILOL IN PATIENTS
WITH SEVERE CHRONIC HEART FAILURE
Benefits of beta-blocker therapy with
carvedilol were evident within a few weeks in patients with advanced HF who
were euvolemic. Benefits were similar
to those obtained by long-term therapy.
Initiation of treatment was well
tolerated when a go-slow, go-low dose was used.
2-10 ASSOCIATION OF SERUM DIGOXIN CONCENTRATION
AND OUTCOMES IN PATIENTS WITH HEART FAILURE
Higher serum concentrations of digoxin
were associated with increased mortality in patients with HF who were in normal
sinus rhythm. The most effective concentration may be 0.5 to 0.8 ng/mL .
2-11 CARDIAC RESYNCHRONIZATION AND DEATH FROM
PROGRESSIVE HEART FAILURE
Recently, cardiac pacemakers have been
modified to correct ventricular dyssynchrony
(left bundle branch block). The
new pacemakers use a left ventricular lead that ensures stimulation of the left
ventricle at, or near, the time of right ventricular depolarization.
Synchronization enhances cardiac function and reduces myocardial oxygen
consumption. It improves exercise capacity, functional class, and quality of
life.
Use of the pacemaker was associated with
a reduction in mortality from 3.5% to 1.7% over 6 months among patients with
advanced HF.
An increased plasma homocysteine level independently predicted
risk of development of CHF in adults without prior myocardial infarction. Another indication for supplementation with
folate?
Cardiac cachexia is common in chronic
HF. It independently predicts a poor outcome. This may assist decisions for
Hospice care. Enalapril delays development of cardiac cachexia in some patients.
4-9 ALDOSTERONE BLOCKADE AND HEART FAILURE
“The addition of aldosterone antagonists to the
regimens of patients with left ventricular systolic dysfunction and ongoing
symptoms of heart failure despite optimal treatment with ACE inhibitors and
beta-blockers can substantially reduce overall mortality and the rate of sudden
death.”
This
review article comments on diastolic
HF and presents new staging and treatment options for systolic HF.
The
diagnosis of diastolic HF is usually made by a clinician who recognizes the
typical signs and symptoms of HF and is not deterred by the finding of normal
systolic function (ie, a normal ejection fraction) on echocardiography.
Echocardiography may also be useful in detecting diastolic filling
abnormalities. Diastolic HF is common.
HF is largely preventable, primarily through control
of risk factors. A new approach to the
classification and progression of systolic HF emphasizes four stages of HF
which differ from the classical NYHA functional classification.
Carvedilol extended survival compared with metoprolol.
However, the challenge in primary care is
not so much which beta-blocker to choose, but judicious use of a beta-blocker
in select patients with heart failure. They are underused in primary care
practice for treatment of heart failure.
9-6 EFFECTS OF CANDESARTAN ON MORTALITY AND
MORBIDITY IN PATIENTS WITH CHRONIC HEART FAILURE
ACE inhibitors have been shown to have the broadest
impact of any drug in cardiovascular medicine, reducing the risk of death,
myocardial infarction, stroke, diabetes, and renal impairment. They benefit
patients with heart failure, left ventricular dysfunction, peripheral vascular
disease, diabetes, stroke, and transient ischemic attacks.
Candesartan, blocks angiotensin II at
the cellular level. Given to patients
with heart failure in addition to
other drugs (including ACE inhibitors) it was associated with reduced
cardiovascular deaths and hospital admissions for heart failure.
Reducing
angiotensin II levels is a basic therapy in cardiovascular disease. ACE
inhibitors have been the standard. Addition of an angiotensin II blocker may
benefit slightly. They should be used when the patients cannot tolerate ACE
inhibitor.
9-7 POLYPHARMACY AND COMORBIDITY IN HEART
FAILURE
Primary care clinicians are responsible for reviewing
medication lists with a goal of eliminating medications that are not known to
provide clear benefits. Little evidence is available to guide polypharmacy in
patients with heart failure and other common conditions
Too many patients, especially the elderly, are taking
too many drugs.
Primary care clinicians should insist
that their patients bring to the office for review all medications they use, including
those prescribed by other physicians, standard drugs bought over the counter,
and herbal nostrums used as “alternative” medicines. This seems difficult for patients to do, but is most important.
The
Killip classification first proposed in 1967:
Killip I—no evidence of HF
Killip II—mild HF, with rales
involving 1/3 or less of the posterior lung fields
and a systolic BP 90 mm or higher.
Killip III—pulmonary
edema with rales involving more than 1/3 of the
posterior lung fields, and systolic
BP of 90 or more.
Killip IV—cardiogenic
shock with any rales and systolic BP under 90.
Killip classification is a powerful independent predictor
of all-cause mortality in patients with non-ST
–elevation acute coronary syndromes as well as in ST-elevation myocardial
infarction.
Age, Killip class, heart rate, systolic BP and ST
depression should receive particular attention in the initial assessment of non-ST –elevation acute coronary
syndromes.
Cardiogenic shock tends to
develop during hospitalization, often secondary to recurrent ischemia or
infarction. Once it develops, it is associated with an extremely high mortality
rate. This delay in presentation of shock in non-ST-elevation acute coronary syndromes creates a fortuitous
window, during which early revascularization may prevent shock.
Diastolic heart failure (DHF) refers to the clinical syndrome of heart failure (HF) with a preserved left ventricular
ejection fraction (0.50 and above) in the absence of major valvular disease.
About a third of patients with HF seen by clinicians have DHF as so defined.
The pathophysiology of DHF is characterized by a low cardiac output resulting from impeded flow into the left ventricle
caused
by thick ventricular walls and a small ventricular cavity.
Clinically, patients with DHF are elderly, more likely
female, and often have a raised BP and associated left ventricular hypertrophy.
However, clinical characteristics by themselves cannot reliably distinguish
systolic from diastolic HF. To make the distinction, it is therefore important
to obtain an imaging study, typically echocardiography, to estimate left
ventricular ejection fraction.
Mechanisms contributing to abnormal left ventricular
diastolic properties include: stiff
large arteries, hypertension, myocardial ischemia, and diabetes.
Acute treatment includes: BP control, relief of ischemia, control of
ventricular rate in patients with atrial fibrillation. Chronic treatment includes restriction of
dietary sodium, and control of hypertension. Treatment is largely empirical.
9-15 EFFECT OF
MAGNETIC VS SHAM-MAGNETIC INSOLES ON PLANTAR HEEL PAIN: A RANDOMIZED CONTROLLED
TRIAL
Magnetic insoles did not benefit any more than sham
insoles. Many patients who use them
will not be convinced despite this well-controlled study.
5-1 “BUILDING”
A HISTORY RATHER THAN “TAKING” ONE
Adopting
a “narrative-based medicine”(NBM) approach
enables the sharing of information between patient and doctor. It incorporates
the patient’s narrative into the sharing process. This article suggests a framework of skills and attitudes that
can act as a foundation to improve the medical interview.
The essence
of a narrative-based approach involves the physician simultaneously attending
to two narratives—one from the biomedical perspective, and one from the
patient’s perspective. Listen to the patient!
An increased plasma homocysteine level independently
predicted risk of development of CHF in adults without prior myocardial
infarction. Another indication for
supplementation with folate?
1-4 GLYCEMIC
EFECTS OF POSTMENOPAUSAL HORMONE THERAPY:
In women with established coronary heart
disease, hormone therapy reduced the incidence of type 2 diabetes by 3.3%
compared with those taking placebo. NNT (4 years to prevent one case) = 30.
And reduced incidence of diabetes by 12%
in those with impaired glucose tolerance at baseline.
Combination
therapy with HRT + alendronate was superior to either drug alone in increasing
BMD.
Estrogen
+ progestin did not reduce the risk for probable dementia in postmenopausal
women age 65 and older.
8-1 BREAST CANCER AND HORMONE-REPLACEMENT
THERAPY IN THE MILLION WOMEN STUDY
This remarkable, country-wide study confirms that
current use of HRT is associated with increased risk of incident and fatal BC.
Between 1996 and 2001, one half of the million women age 50-64 in this UK
cohort were using HRT.
The risk is substantially less for estrogen-alone than
for E-P combinations.
Use of HRT by women aged 50-64 in the UK over the past
decade is estimated to have resulted in 20 000 extra cases of BC; 15 000 of
these associated with E-P use; 5000
with use of estrogen alone. (Ie,
progestins are the major culprit.)
Women who are presently taking estrogen-progestin may
be told there is one additional chance in 150 of an invasive BC over 5 years;
and one additional chance in 800 if they are taking estrogen alone.
Risk increases with duration of use. Past users (5 or
more years previously) were not at increased risk.
8-2 ESTROGEN PLUS PROGESTIN AND THE RISK OF
CORONARY HEART DISEASE.
E-P, in standard dose, does not confer cardiac
protection. It may slightly increase risk of CHD, especially during the first
year of use. Primary care clinicians may consider prescribing low-dose aspirin
for primary prevention, at least during the first year. Treatment to improve
lipid profiles reduces risk.
E-P should not be prescribed for the prevention of
cardiovascular disease.
Any possible increase in incidence of CHD (about 6
extra cases per 10 000 patient-years) is minor compared with the risk for breast
cancer.
Oral, but not transdermal ERT, was
associated with risk of VTE in postmenopausal women. Transdermal administration
avoids the first pass through the liver and blunts production of thrombogenic
proteins by the liver.
A good example of the advantages of
transdermal application of drugs.
2-6 ADDING A TEST FOR HUMAN PAPILLOMA VIRUS DNA
TO CERVICAL-CANCER SCREENING
Virtually
all squamous-cell cervical carcinomas contain one of eighteen types of human
papilloma virus (HPV). The relative
risk of cervical cancer associated with persistent infection with high-risk
types of HPV (especially types 16 and 18) is higher than the risk of lung
cancer associated with smoking.
The
discovery that continued presence of tumor-producing HPV is necessary for
development of cervical cancer is revolutionizing our approaches to screening
and prevention. An obvious corrrelary is that the absence of infection means
that the risk of cervical cancer is negligible.
12-6 INTRA-ARTICULAR HYALURONIC ACID IN TREATMENT
OF KNEE ARTHRITIS
“Based on the findings of this
meta-analysis, intra-articular hyaluronic acid has, at best, modest
efficacy
in the treatment of knee osteoarthritis. This effect . . . “is equivalent to
the effect of NSAIDs over that of acetaminophen, an effect that itself remains
controversial.” .” “Our findings
suggest the controversy surrounding the efficacy of intra-articular hyaluronic
acid is justified and the best evidence does not support its efficacy.”
At least 17 of the 22 trials were
industry sponsored. Others have suggested that findings from industry-sponsored
trials compared with those that were otherwise funded showed that research
funded by pharmaceutical companies was more likely to have outcomes favoring
the sponsor.
All 22 studies reported improvement of
pain in the intra-articular placebo groups. Placebo injections may have
efficacy for treating knee OA. The investigators calculated that
intra-articular placebo accounted for 79% of the efficacy of intra-articular
hyaluronic acid.
“This supports our hypothesis that the majority of the effect of
intra-articular hyaluronic acid is an intra-articular placebo effect.”
Publication
bias may overestimate the effect. Compared with lower-molecular-weight
hyaluronic acid, the higher-molecular weight hyaluronic acid may be more
efficacious, but heterogeneity of studies limits definitive conclusions.
I doubt this study will deter
enthusiasts from using HA. Individual patients who have apparently obtained
relief may insist on continuing.
The only way an individual’s response
can be accurately determined is by an N-of-one trial.
I
doubt this would be feasible considering the ethical issues involved.
Initiation of antihypertension treatment with ACE
inhibitor in older men appeared to lead to better outcomes than diuretics
despite similar reductions of BP. Patients often required 2 or more drugs.
NNT to benefit one male patient over 1
year = 270. No benefit in females.
2-3 INITIAL TREATMENT OF HYPERTENSION
On the basis of available data,
diuretics or beta-blockers remain appropriate for the initial treatment of
uncomplicated hypertension.
“In
patients over age 65, morbidity and mortality from cardiovascular disease are
reduced when systolic blood pressure is lowered to a level below 160 mm Hg.
Whether levels below 140 mm Hg provide additional protection is unclear.” “Optimal blood pressure targets remain to be
determined, particularly for elderly patients.”
Primary care clinicians should develop a
set initial drug protocol for treating long standing (ie, lifetime) illnesses
which require long-term costly medication. We should aim to provide the least
expensive, least toxic drugs and drug doses, which are easiest to take, and
more likely to lead to compliance. The editor of Practical Pointers suggests a
protocol.
In absolute terms, benefits were small, with absolute
differences between groups of 0.6% to 2.1%.
(NNT [to benefit one patient over 3 years] = 47 to 166.)
“Reaction to the 36% relative reduction in the primary
endpoint and the other benefits observed in ASCOT
may
need to be tempered by consideration of the absolute risk reduction of a
coronary event of 3.4 per 1000 patients-years.” “There are clearly financial implications.” (As well as adverse events from the drug. RTJ)
Provides
new guidelines and key messages:
Individuals with a systolic 120-139 or a diastolic 80–90 should be
considered as pre-hypertensive. They
require health-promoting lifestyle modifications to prevent CVD.
The
committee recognizes that the responsible physician’s judgment remains
paramount.
5-6 HEALTH OUTCOMES ASSOCIATED WITH VARIOUS
ANTIHYPERTENSIVE THERAPIES USED AS FIRST-LINE AGENTS
Low-dose
diuretics are the treatment of first choice for patients with uncomplicated
hypertension who require drug treatment.
They are the most effective drugs for preventing cardiovascular disease
morbidity and mortality.
6-9 PROGNOSTIC VALUE OF AMBULATORY BLOOD
PRESSURE RECORDINGS IN PATIENTS WITH TREATED HYPERTENSION
In patients with treated
hypertension, a higher ABP, systolic or diastolic, predicted cardiovascular
events even after adjustment for classic risk factors including office BP. As
judged by ABP, office BP may be misleading.
6-10 AMBULATORY BLOOD-PRESSURE MONITORING IN
CLINICAL PRACTICE
24-hour ABP monitoring yields readings during all the
patient’s activities, and gives a far better representation of the “blood
pressure burden” than that obtained during office visits.
ABP should be used more often in clinical practice.
“For those whose ambulatory blood pressure is truly
normal (< 130/80) despite an elevated office blood pressure, and in whom
there is no evidence of other cardiovascular risk factors of target-organ
disease, avoidance of unnecessary drug therapy would be a clear benefit of the
monitoring procedure.”
6-2 VALUE OF
LOW DOSE COMBINATION TREATMENT WITH BLOOD PRESSURE LOWERING DRUGS
Combining low dose drug treatment for hypertension
increases efficacy and reduces adverse effects. Three drugs at half dose are
estimated to lower risk of stroke by 63% and ischemic heart disease by 46% at
age 60-69.
This study estimated the effects of
strategies based on different drug classes and on those targeting different BP
goals on the risks of major cardiovascular events and death.
Treatment with any commonly-used regimen reduces the
risk of total major cardiovascular events.
A larger reduction in BP reduces risk of total
cardiovascular events. BP-lowering is a major component of the benefit
conferred by the regimens investigated.
There was a larger reduction in stroke and total major cardiovascular
events from regimens aimed at a lower BP goal.
ACE-inhibitor-based regimens benefit across a wide
range of hypertensive and non-hypertensive patients
who
are at high risk for cardiovascular disease.
ACE inhibitor or diuretic or beta-blocker are much
more effective in preventing heart failure than
calcium
antagonists.
For stroke, there is a greater effect of regimens
based on calcium antagonists than those based on
diuretics
or beta-blockers, but the results were of borderline significance.
Reductions in systolic BP of 2, 4, 6, 8, and 10 mmHg
were associated with lower risk of stroke, major
cardiovascular
disease, coronary heart disease, cardiovascular death, and total mortality.
A great many
older adults remain at high risk of heart disease and stroke from untreated
isolated systolic hypertension (ISH; systolic
> 140, diastolic < 90).
Treatment of ISH is associated with clear benefits. The Systolic Hypertension in the Elderly Program ( JAMA 1991) demonstrated a 36% reduction in stroke among participants
assigned to active BP treatment. The Systolic Hypertension in Europe trial (Lancet 1998) reported that active
treatment of ISH significantly reduced the incidence of dementia. And also exerted a strong effect in
preventing heart failure.
This subset of the SHEP study was begun
after closure of the original study. It compared risk of death and
cardiovascular event rates in actively treated patients with ISH, vs placebo
controls, and normotensive controls. Follow up was up to 14 years. Event rates
were decreased by 21% in the actively treated group.
Early treatment, before advanced
atherosclerosis develops, results in the best long-term outcomes. The
prevalence of subclinical atherosclerosis in individuals with ISH is high
compared with normotensive controls. Active treatment of ISH is associated with
slower progression of subclinical atherosclerosis. The development of
atherosclerosis with ISH likely adds to the acceleration of vascular
stiffening, which is the underlying cause of ISH. Thus, early treatment may
slow not only the progression of atherosclerosis, but progression of ISH as
well.
Severe ISH may be difficult to control,
requiring multiple drugs.
12-3 OVERCOME CLINICAL INERTIA TO CONTROL
SYSTOLIC BP
It is clear that in individuals younger
than age 50, diastolic BP (DBP) is a
better predictor of future complications of hypertension than in older
individuals. For those older than 50,
systolic BP (SBP) is a better
predictor. Most persons with hypertension are older than 50. For these patients
control of SBP is a high priority, even in the face of a normal DBP.
“Systolic blood pressure alone correctly
classifies hypertensive status in about 98% of adults.”
Most patients with elevated SBP need
aggressive treatment to reach the evidence-based goal of less than 140. We are
beginning to see that 130 and even 120 is some groups such as those with diabetes,
congestive heart failure, and chronic kidney disease is a beneficial goal. SBP
in these mostly older patients is the variable that indicates the need for more
intensive therapy.
4-12
EFFECT OF MULTIVITAMIN AND MINERAL SUPPLEMENT ON INFECTION AND QUALITY OF LIFE
A daily multivitamin-mineral supplement was associated
with reduced incidence of patient-reported infection and related absenteeism in
the subset of patients with type 2 diabetes who had a high prevalence of
subclinical micronutrient deficiency.
In the elderly, vaccination against influenza was associated with large
reductions in numbers of hospitalizations from heart disease, cerebrovascular
disease, as well as pneumonia and influenza. Risk of death was reduced by about
50%.
Flu vaccination is one of the most
cost-effective health interventions. Primary care clinicians bear
responsibility for increasing uptake by the general population.
6-12 EFFECTIVENESS OF NEURAMINIDASE INHIBITORS
IN TREATMENT AND PREVENTION OF INFLUENZA A AND B
Evidence consistently supports the view that zanamivir
(Relenza) and oseltamivir (Tamiflu) are clinically effective in
treating and preventing flu. Evidence is limited for treatment of certain
populations as well as for prevention
strategies. The numbers needed to treat to prevent one person from developing
flu may be high.
Choosing individuals for whom the drugs are indicated
would be a clinical-judgment call, depending largely on cost, personal
preference, and likelihood of severe complications from flu.
The drugs are no substitute for vaccination. They may
be adjunctive therapy on occasion.
10-9 INHALED INSULIN PROVIDES IMPROVED GLYCEMIC
CONTROL IN PATIENTS WITH
TYPE
2 DIABETES MELLITUS INADEQUATELY CONTROLLED WITH ORAL AGENTS.
Recently, a
dry powder inhaled insulin (IN-I) system has been developed. It
provides a new method of treatment. The pulmonary route exploits the large
vascular bed and permeability of the alveoli to deliver insulin directly into the
blood stream. IN-I has a rapid onset of action, actually faster than injected
regular insulin and insulin lispro. Its duration of action is about 6 hours.
Pre-meal inhaled powdered insulin (IN-I) added to oral agents produced
a significantly greater reduction in HbA1c than oral agents alone (metformin or
sulfonylurea, or both)—a mean reduction in HbA1c of 2.3 %. HbA1c remained stable in the control
group—about 10%
One third of the IN-I
+ oral agents group achieved a HbA1c less than 7% vs none in the oral
agents alone group. (Mean HbA1c dropped from about 10% to 7.5% in the IN-I
group.)
Fasting plasma glucose improved significantly.
This means of administration will eliminate the fear of
injections. Patient satisfaction was high--97% opted to continue in a 1-year
extension of the therapy.
This is an early proof of concept study.
Primary care clinicians will watch for developments with great interest. Cost
is to be determined.
6-7 INTENSIVE DIABETES THERAPY AND CAROTID
INTIMA-MEDIA THICKNESS IN TYPE 1 DIABETES MELLITUS
Intensive therapy over an extended time
resulting in a mean HbA1c of 7.2% decreased progression of intima-media
thickness. Evidence that tight control may delay macro-vascular disease.
8-9 CARDIOVASCULAR RISK FACTORS AND INCREASED
CAROTID INTIMA-MEDIA THICKNESS IN HEALTHY YOUNG ADULTS
Atherosclerosis is a slowly progressive process
possibly starting at a young age. Preventive measures taken early in life might
postpone the development of atherosclerosis and decrease risk of clinical
cardiovascular disease (CVD).
Unfavorable cardiovascular risk factors (cigarette
smoking, diabetes, dyslipidemia, and hypertension) were related to greater CIMT
in young adulthood. Effort to change
modifiable risk factors early in life may retard development of atherosclerosis
and the onset of clinical cardiovascular disease later in life.
High dose simvastatin over 2 years reduced combined
carotid/femoral IMT in more than two thirds of patients. The largest effect was
on the femoral artery. This degree of reduction of IMT. . . “will likely have a
significant clinical impact on the prevention of coronary artery disease”.
Primary care clinicians might easily extrapolate these
results to other patients with high cholesterol levels.
Atherosclerosis
is reversible.
ISOLATED SYSTOLIC HYPERTENSION
A great many
older adults remain at high risk of heart disease and stroke from untreated
isolated systolic hypertension (ISH; systolic
> 140, diastolic < 90).
Treatment of ISH is associated with clear benefits. The Systolic Hypertension in the Elderly Program ( JAMA 1991) demonstrated a 36% reduction in stroke among participants
assigned to active BP treatment. The Systolic Hypertension in Europe trial (Lancet 1998) reported that active
treatment of ISH significantly reduced the incidence of dementia. And also exerted a strong effect in
preventing heart failure.
This subset of the SHEP study was begun
after closure of the original study. It compared risk of death and
cardiovascular event rates in actively treated patients with ISH, vs placebo
controls, and normotensive controls. Follow up was up to 14 years. Event rates
were decreased by 21% in the actively treated group.
Early treatment, before advanced
atherosclerosis develops, results in the best long-term outcomes. The
prevalence of subclinical atherosclerosis in individuals with ISH is high
compared with normotensive controls. Active treatment of ISH is associated with
slower progression of subclinical atherosclerosis. The development of
atherosclerosis with ISH likely adds to the acceleration of vascular
stiffening, which is the underlying cause of ISH. Thus, early treatment may
slow not only the progression of atherosclerosis, but progression of ISH as
well.
Severe ISH may be difficult to control,
requiring multiple drugs.
12-3 OVERCOME CLINICAL INERTIA TO CONTROL
SYSTOLIC BP
It is clear that in individuals younger
than age 50, diastolic BP (DBP) is a
better predictor of future complications of hypertension than in older
individuals. For those older than 50,
systolic BP (SBP) is a better
predictor. Most persons with hypertension are older than 50. For these patients
control of SBP is a high priority, even in the face of a normal DBP.
“Systolic blood pressure alone correctly
classifies hypertensive status in about 98% of adults.”
Most patients with elevated SBP need
aggressive treatment to reach the evidence-based goal of less than 140. We are
beginning to see that 130 and even 120 is some groups such as those with
diabetes, congestive heart failure, and chronic kidney disease is a beneficial
goal. SBP in these mostly older patients is the variable that indicates the
need for more intensive therapy.
2-4 THE
PREVENTION AND TREATMENT OF JET LAG.
The Cochrane Review concludes that 2 to 5 mg
melatonin taken at bedtime at the new destination is effective, and may be
worth repeating for the next two to four days.
The article gives other suggestions for
minimizing both travel fatigue and jet lag.
11-1 THE CRUCIAL LINK BETWEEN LITERACY AND
HEALTH.
In 1993, the National Adult Literacy
Survey reported that half of adult Americans have limited literacy skills. They
struggle to reliably complete many simple daily tasks such as completing forms,
reading signs, or using transportation schedules. At least as many patients, then, must struggle with health care’s
many forms, educational materials, and directions.
“The physician should never presume that a patient is
literate.” Even the most poised and articulate persons may have trouble
reading. People with reading problems are unlikely to step forward and ask for
help.
One method to improve communication is called “closing
the loop”. The physician asks the
patients to restate the message in their own words. This teach-back method assures the physician that the patient
understands.
This is a good example of the large gap between
“evidence based medicine” (EBM) and
the real world of primary care. I do not recall reading in the entrance
criteria of trials that all subjects were medically literate--nor in the
exclusion criteria that those with poor literacy were excluded. I believe exclusion is automatic.
Randomized trials, the basis of EBM, deal with a
well-defined group of subjects. Patients seen in primary care often do not fit
into the group. This will require the clinician to use her best clinical
judgment to fit the circumstances. As important as EBM is, I believe it does
not apply to a large majority of clinic patients. RTJ
11-6 EFFECT OF FIRMNESS OF MATTRESS ON CHRONIC
NON-SPECIFIC LOW-BACK PAIN
Randomized, double-blind, controlled, multicenter
trial assessed 313 adults (median age 44) who had
chronic
low-back pain. None had referred pain. All complained of backache while lying
in bed and on arising.
At 90 days, patients using the medium-firm mattress
were about twice as likely to improve as were patients
using
firm mattresses.
Outcomes for less pain in bed (Odds Ratio = 2.4), less
pain on arising (OR = 1.93) and less disability
(OR
= 2.1) as compared with the firm mattress.
Throughout the study, the medium-firm group had less
daytime low-back pain.
“The results of this study suggest that, although
psychosocial factors have an effect on disability, some
biomechanical
factors also have an effect and should be taken into consideration.”
How can the primary care clinician apply these
results? I believe it comes down to a N
of 1 study. If possible, patients may try a variety of mattresses. This may not
be practical. If the patient considers his mattress to be firm, a less firm one
may be tried. If he considers it to be soft, a firmer one may be tried.
9-15 EFFECT OF
MAGNETIC VS SHAM-MAGNETIC INSOLES ON PLANTAR HEEL PAIN: A RANDOMIZED CONTROLLED
TRIAL
Magnetic insoles did not benefit any more than sham
insoles. Many patients who use them
will not be convinced despite this well-controlled study.
4-4 MAMMOGRAPHIC SCREENING FOR BREAST CANCER.
Eight trials have been published. In patients between
ages 50 and 69, all reports of studies comparing screening with no screening
showed protective effects of screening—a statistically significant 20 to 35 percent
reduction in mortality from BC.
The downside: False positive results necessitate
further investigation. Nationally, an average of 11% of screening mammograms are read as abnormal. BC is subsequently
found in about 3% of these women ( 0.3% of all mammograms). Thus, a woman has
about a 10% chance of a false positive result with each mammogram. Because
women are screened repeatedly, the risk of a false positive increases over
time. One study estimated that, after 10 mammograms, about half of women age 40
to 64 will have had a false positive leading to needle biopsy or open biopsy in
about 20%. The malpractice climate in the USA may work to increase the numbers
of false positive reports.
7-7 WOMEN NEED BETTER INFORMATION ABOUT ROUTINE
MAMMOGRAPHY
The public should be told about all the outcomes of
screening in terms it can understand. Surgical and psychological morbidities
are important outcomes. Unnecessary treatments arise from overdiagnosis. This
includes biopsies, segmental excisions, mastectomies, and even
radiotherapy. “Until tools are
developed that are capable of measuring a wide variety of outcomes, we cannot
weigh the evidence satisfactorily.”
“The age at which the trade-off between benefit and
harm becomes acceptable is a subjective judgment that cannot be answered on
scientific grounds.” Most women who are screened have not been educated about
the uncertainties.
The close association of type 2 diabetes with
cardiovascular disease (CVD) led to
the hypothesis that the two arise from a common antecedent. This concept has
been codified by the WHO and others as “the metabolic syndrome”. This diagnosis
might hold the promise for enhanced prevention of diabetes and CVD.
The metabolic syndrome: Obesity (especially central obesity); Dyslipidemia (especially high triglycerides and low
HDL-cholesterol); Hyperglycemia; Hypertension
Is the
risk associated with a cluster of all 4 traits likely to exceed the sum
of the four traits? I believe. .
. “The whole is greater than the sum of
the parts”?
1-9 PROPHYLACTIC TREATMENT OF MIGRAINE WITH AN
ANGIOTENSIN-II RECEPTOR BLOCKER
In this study, the angiotensin II
blocker, candesartan, provided effective migraine prophylaxis with tolerability
comparable to that of placebo.
10-16 PROGNOSTIC VALUE OF MYELOPEROXIDASE IN PATIENTS
WITH CHEST PAIN
Clinical criteria, ECG criteria, and conventional
laboratory tests, including troponin T, often do not adequately predict the
risk of cardiovascular events in patients presenting with acute coronary
syndromes.
C-reactive protein and other markers have been advocated as
a more accurate means of gauging risk,
but
additional tools are needed to predict vulnerability of coronary arteries to
major events in the near term. Myeloperoxidase is an excellent candidate. It
predicts cardiovascular risks independently of C-reactive protein and other
markers of inflammation.
“Our findings suggest that myeloperoxidase serves as a
marker of the vulnerable plaque and one that
can be
used to identify patients at imminent
risk for major adverse cardiac events, independently of evidence of myocardial
necrosis.”
A single measurement of myeloperoxidase independently
predicted early risk of myocardial infarction, as well as the risk of major
adverse cardiac events in the ensuing 30 days and 6 months. It identified
patients at risk in the absence of myocardial necrosis.
This
is a preliminary report. Watch for developments.
Adding troponin levels as criterion for
the diagnosis identified many more patients as having an acute myocardial
infarction.
1-12 PRIMARY ANGIOPLASTY VERSUS INTRAVENOUS
THROMBOLYTIC THERAPY FOR ACUTE MYOCARDIAL INFARCTION.
Primary PTCA is more effective than
thrombolytic therapy for treatment of ST-elevation AMI.
9-2 ORAL XIMELAGATRAN FOR SECONDARY PROPHYLAXIS
AFTER MYOCARDIAL INFARCTION
In patients with a recent MI, long term treatment with
ximelagatran, combined with aspirin, was more effective than aspirin alone in
reducing frequency of major cardiovascular events. [NNT (for 6 months to benefit one) = 33]
Ximelagatran is the first of a
new class of oral direct-thrombin
inhibitors under investigation. It is rapidly metabolized to its active
form, melagatran. It is stable over time. Its metabolism is unaffected by age,
sex, body weight, or ethnic origin. It is not affected by the hepatic
cytochrome P450 enzyme system, thus providing a low potential for drug-drug
interactions. There are no relevant
food or alcohol interactions.
“Melagatran’s pharmacokinetics are unchanged and the pharmacodynamic
properties show only minor additive effects when oral ximelagatran and
acetylsalicylic acid are given concomitantly.”
Ximelagatran has undergone extensive assessment in
patients with venous thromboembolism and atrial fibrillation. It has a rapid
onset of action, achieves a peak level within 2 hours, and has a half-life of 4
hours. It is administered twice daily. There is no need of monitoring and dose adjustments. (Monitoring of liver and kidney
function is required. RTJ)
Ximelagatran is primarily excreted by the kidney. Data on patients with
kidney dysfunction are limited.
With the 24 mg BID dose, the bleeding rate was low,
and high concentrations of alanine amino transferase occurred less frequently
(7%).
“It is good news that the more than half
century wait of new and improved oral antithrombotics finally appears to be
ending.”
10-16 PROGNOSTIC VALUE OF MYELOPEROXIDASE IN
PATIENTS WITH CHEST PAIN
Clinical criteria, ECG criteria, and conventional
laboratory tests, including troponin T, often do not adequately predict the
risk of cardiovascular events in patients presenting with acute coronary
syndromes.
C-reactive protein and other markers have been advocated as
a more accurate means of gauging risk,
but
additional tools are needed to predict vulnerability of coronary arteries to
major events in the near term. Myeloperoxidase is an excellent candidate. It
predicts cardiovascular risks independently of C-reactive protein and other
markers of inflammation.
“Our findings suggest that myeloperoxidase serves as a
marker of the vulnerable plaque and one that
can be
used to identify patients at imminent
risk for major adverse cardiac events, independently of evidence of myocardial
necrosis.”
A single measurement of myeloperoxidase independently
predicted early risk of myocardial infarction, as well as the risk of major
adverse cardiac events in the ensuing 30 days and 6 months. It identified patients at risk in the
absence of myocardial necrosis.
This
is a preliminary report. Watch for developments.
Angiotensin-converting-enzyme inhibitors (ACE-I) do not completely block
production and effects of angiotensin II. Likewise, angiotensin-receptor
blockers (ARB) do not completely
block angiotensin II. But, they do act differently. Investigators have
speculated that adding the two would produce greater benefits than either one
used alone.
In this study, however, use of the two
drugs together did not benefit any more than either used alone. Valsartan is as
effective as captopril (but not more effective) as measured by risk of death in
patients who are at high risk for cardiovascular events after a myocardial
infarction. The combination increased adverse effects without improving
survival.
I abstracted this study because it contrasts with
other studies reported in Practical
Pointers. Doubt remains about the efficacy of combined ACE inhibitors and
ARBs. See “Effects of Candesartan on Mortality and Morbidity in Patients with
Chronic Heart Failure” Practical Pointers September 2003. The
study reported a slight benefit when candesartan was added to ACE inhibitors.
(NNT = 25 to 50) Hyperkalemia,
hypotension, and increased creatinine levels occurred more commonly in the
combined group.
I believe primary care clinicians should avoid the
combination until clarification is available. ARB may be used when ACE
inhibitors are not tolerated. RTJ
NON-ALCOHOLIC FATTY LIVER DISEASE
6-8 NON-ALCOHOLIC FATTY LIVER DISEASE: An Unrecognized Cause Of Cryptogenic
Cirrhosis
Cryptogenic cirrhosis (CC) is a significant contributor to liver related morbidity.
Non-alcoholic fatty liver disease (NAFLD)
is the most common cause of CC. The diagnosis of cirrhosis in these patients is
usually delayed by almost a decade and is often not established until after the
patient develops hepatocellular carcinoma or other complications of advanced
liver disease. Once cirrhosis is diagnosed, mortality is greater than that of
hepatitis C virus related cirrhosis.
Existing evidence, albeit scant, suggests that NAFLD
is a spectrum, progressing from hepatic steatosis to non-alcoholic
steatohepatitis, and then on to cirrhosis. Over 6 million US adults have NAFLD,
and 640 000 may have cirrhosis. This may exceed the numbers infected with
hepatitis C. Prognosis is just as bad.
Diagnosis remains one that is established only after
other causes of chronic liver disease have been excluded. NAFLD can be more
readily suspected if the patient is obese and has diabetes. Primary care
clinicians have an opportunity for prevention by controlling obesity, lipids,
and diabetes.
NONSTEROIDAL
ANTI-INFLAMMATORY DRUGS (NSAIDs )
8-14 EXPOSURE TO NON-STEROIDAL ANTI-INFLAMMATORY
DRUGS DURING PREGNANCY AND RISK OF MISCARRIAGE
NSAIDs and aspirin were associated with an increased risk of
miscarriage. Acetaminophen was not.
1-10 OBESITY AND ADULTHOOD AND ITS CONSEQUENCES
FOR LIFE EXPECTANCY
Obesity in adulthood is associated with
decreases in life expectancy among men, women, smokers and non-smokers. (Up to
7 years of life lost.) Combined
smoking/obesity doubles risk.
4-6 WEIGHT LOSS COUNSELING REVISITED.
If treatment success is defined exclusively as
attaining ideal weight after losing a large amount of weight during a short
term intervention, obesity treatment will almost certainly fail. “Obesity must
be recognized as a chronic condition for which no cure can reasonably be
expected.” However, even small weight
loss can reduce obesity-associated risk factors for chronic diseases such as
diabetes and hypertension.
Physicians must remain non-judgmental and empathetic
and distinguish between a “weight problem” and a “patient with a weight
problem”. Recognize the challenges and
frustrations the patient faces. Many obese
patients, especially women, “have come
to expect rejection and disparagement . . . and are favorably surprised when
they receive the consideration that physicians usually accord patients”.
An initial goal of weight loss of 10% of initial
weight during a 6-month period is achievable and can significantly reduce
obesity-related conditions. Most patients do not reach their ideal weight.
Acceptance of a modest weight-loss is critical to prevent future
disappointment. Emphasize the important health benefits and achievability of
smaller reductions and help the patient accept a modest weight loss goal at the
start of treatment. .
Obesity is a chronic condition requiring long-term
care. For those not willing or able to lose, clinicians can help the patient to
avoid further weight gain.
Ultimately, prevention is the goal.
4-7 EFFICACY AND SAFETY OF LOW-CARBOHYDRATE
DIETS
Despite the abundance of lay literature on the topic
of low-carbohydrate (Atkins’) diets, marked discordance exists between the
knowledge needed to guide dietary choices and the information that is available
in the medical literature.
There is insufficient evidence to make
recommendations for or against the use of low-carbohydrate diets. Among the published
studies, participant weight loss while using low-carbohydrate diet was
principally associated with decreased caloric intake and increased duration,
but not with reduced carbohydrate content.
4-8 LOW-CARBOHYDRATE DIETS AND REALITIES OF
WEIGHT LOSS
“Without carbohydrate-containing foods (eg, breads)
less fat is ingested because few people eat much fat by itself.” Thus, low-carbohydrate diets reduce calorie
intake.
A potential advantage of very
low-carbohydrate diets is that removing sweets from the diet can reduce the
gustatory stimulation that sweets produce. (This gustatory stimulation by
sweets easily leads to over consumption.)
The low-carbohydrate diets do reduce consumption of
high fructose soft drinks, but do not deal with the preference that many humans
have for sweets. “The aspect of carbohydrates as a preference in the diet is
one that still needs to be addressed.”
The broader issue of whether a unique diet exists that
will produce long-term weight loss has yet to be evaluated. That “a calorie is
a calorie” has been reaffirmed. The question of whether patients can adhere
more easily to one type of diet or other remains to be answered.
7-3 STRUCTURAL AND SYMPTOMATIC EFFICACY OF
GLUCOSAMINE AND CHONDROITIN IN KNEE OSTEOARTHRITIS
Evidence that glucosamine benefits symptoms and slows
joint deterioration.
The purity and dose of these
over-the-counter preparations are not regulated by the FDA.
Primary care clinicians may be willing
to prescribe it despite regulation by the FDA.
12-6 INTRA-ARTICULAR HYALURONIC ACID IN TREATMENT
OF KNEE ARTHRITIS
“Based on the findings of this
meta-analysis, intra-articular hyaluronic acid has, at best, modest
efficacy
in the treatment of knee osteoarthritis. This effect . . . “is equivalent to
the effect of NSAIDs over that of acetaminophen, an effect that itself remains
controversial.” .” “Our findings
suggest the controversy surrounding the efficacy of intra-articular hyaluronic
acid is justified and the best evidence does not support its efficacy.”
At least 17 of the 22 trials were
industry sponsored. Others have suggested that findings from
industry-sponsored
trials compared with those that were otherwise funded showed that research
funded by pharmaceutical companies was more likely to have outcomes favoring
the sponsor.
All 22 studies reported improvement of
pain in the intra-articular placebo groups. Placebo injections may have
efficacy for treating knee OA. The investigators calculated that
intra-articular placebo accounted for 79% of the efficacy of intra-articular
hyaluronic acid.
“This supports our hypothesis that the majority of the effect of
intra-articular hyaluronic acid is an
intra-articular
placebo effect.”
Publication
bias may overestimate the effect. Compared with lower-molecular-weight
hyaluronic acid, the higher-molecular weight hyaluronic acid may be more
efficacious, but heterogeneity of studies limits definitive conclusions.
I doubt this study will deter
enthusiasts from using HA. Individual patients who have apparently obtained
relief may insist on continuing.
The only way an individual’s response
can be accurately determined is by an N-of-one trial.
I
doubt this would be feasible considering the ethical issues involved.
Combination
therapy with HRT + alendronate was superior to either drug alone in increasing
BMD.
9-17
PARATHYROID HORMONE PLUS ALENDRONATE—A Combination That Does Not Add Up
It would
be plausible to assume that the effect of a bisphosphonate + parathyroid
hormone would be additive, since their mechanisms of action differ.
Unfortunately, this is not the case.
Disappointing !
Apparently, alendronate impairs the anabolic activity
of parathyroid hormone.
1-14 OUTDATED DRUGS MAY BE USEFUL
This
letter to the editor brings up an important practical point. Should we discard
all drugs when they become outdated?
The correspondent believes that many
drugs maintain potency long after expiration date. In developing countries and
“free” clinics in the USA, the choice may be “outdated” or “none at all”.
Perioperative (before and after surgery) use of a
COX-2 inhibitor was effective component of multimodal analgesia. It reduced
opioid consumption, pain, vomiting, and sleep disturbance. It shortened the
time physical therapy was needed to achieve effective joint range of motion.
Pain is the 5th monitored vital sign.
Efficient management of pain improves postoperative clinical outcomes. After
total knee arthroplasty (TKA), inadequate control of postoperative pain is
associated with poor functional recovery.
Surgical trauma induces cyclo-oxygenase
2 (COX-2) which then promotes
synthesis of prostaglandins that sensitize peripheral nocioceptors and mediate
central sensitization. NSAIDs as well as opioids decrease this inflammatory
response. Pre-operative
administration of NSAIDs may be effective by establishing a sufficient tissue
NSAID concentration to inhibit early production of prostaglandins before the
onset of tissue trauma, thus attenuating the development do hyperalgesia.
I wonder if sports medicine enthusiasts
might offer pre-game COX-2 inhibitors to players (eg, football) who might be
subject to injury during a game. This might lessen the period of disability if
a serious injury should occur.
9-17
PARATHYROID HORMONE PLUS ALENDRONATE—A Combination That Does Not Add Up
It would
be plausible to assume that the effect of a bisphosphonate + parathyroid hormone
would be additive, since their mechanisms of action differ. Unfortunately, this
is not the case. Disappointing !
Apparently, alendronate impairs the anabolic activity
of parathyroid hormone.
PATIENTS RELATIONSHIP WITH THEIR DOCTORS
9-13 PATIENTS PUT THEIR RELATIONSHIP WITH THEIR
DOCTORS AS SECOND ONLY TO THAT OF THEIR FAMILIES
A
new international study given at the World Medical Association annual assembly
reported that, although the doctor-patient relationship has become less
paternalistic, it still holds a central and trusted place in society. The authors warn that, to keep this status,
doctors will need to measure up to patients’ higher expectations of care.
“The patient-physician relationship is part of the
critical underpinnings of stable societies.”
It is still a privilege to be a physician.
8-14 EXPOSURE TO NON-STEROIDAL ANTI-INFLAMMATORY
DRUGS DURING PREGNANCY AND RISK OF MISCARRIAGE
NSAIDs and aspirin were associated with an increased risk of
miscarriage. Acetaminophen was not.
PREMENSTRUAL DYSPHORIC DISORDER
1-5 PREMENSTRUAL DYSPHORIC DISORDER
Selective serotonin reuptake inhibitors
(SSRI) are first-line agents for PDD.
Several trials have demonstrated they are superior to placebo for treatment of
the emotional and physical symptoms.
Fluoxitine (Prozac) and Sertraline (Zoloft) are the most
studied. A 20 mg dose of fluoxitine is as effective as the 60 mg and has fewer
adverse effects and fewer dropouts. SSRIs may be given continuously or for two
weeks before the expected period. Luteal phase administration has been
effective.
8-3 IS OPPORTUNISTIC DISEASE PREVENTION IN THE
CONSULTATION ETHICALLY JUSTIFIABLE?
Consultations in primary health care
have been suggested as an ideal setting for health promotion and disease
prevention. Doctors are expected to discuss preventive measures even when they
are not among the reasons for the consultation. Opportunistic preventive
medicine is considered a part of good medical practice. This article asks. .
.Is this ethically justifiable?
The authors argue that doctors should
maintain a clear focus on each patient’s reasons for seeking help rather than
be distracted by an increasing list of preventive measures. They maintain that,
from a moral point of view, initiatives to improve health among people who are
currently free of symptoms is fundamentally different from curative
medicine—the condition for which the patient consults.
Physicians who offer a screening test carry a
considerable responsibility. They must offer enough information about risks and
benefits in order to enable the patient to give informed consent. Informed consent presupposes an
understanding of the limitations of the screening test. Every test carries a
chance of misclassification of disease. A false positive test may result in
further interventions that do not benefit the patient, and may cause harm.
“Once medical risk has been passed on to a person, it
cannot be retracted. Respect for autonomy should therefore also honor the
person’s right not to be
opportunistically confronted with knowledge about biomedical risks that are
unrelated to his or her reasons for seeing the doctor.”
“As the list of accessible preventive tests lengthens
and thresholds for intervention are lowered, a doctor who adheres to all
recommendations for provision of preventive services may ultimately be able to
find something abnormal in everybody.”
Think twice before advising screening tests.
4-1 SCREENING FOR PROSTATE CANCER
“Few
issues are as controversial.” Adequate
evidence is absent.
An
approach that recommends men should be fully informed of risks and benefits of
screening and then asked to make up their own minds is disingenuous when it is
clearly difficult for specialists advisors to know the best approach. At
present patients are offered an “informed” choice. But, the most informed
observer can point only to uncertainty.
“Tests
have no meaning without clarity of purpose.”
The main aim of PC screening is not to detect cancerous tissue, but to
identify men who are asymptomatic and would otherwise die or be disadvantaged
by untreated PC in the future, perhaps in 10 to 15 years.
The weakness of the case for
generalized screening rests on the poorly defined nature of the group
identified for treatment. Current predictive values are poor. We still do not
understand the natural history of PC well enough to distinguish those in whom
disease is likely to progress from those whose pathology presents limited risk
in terms of function and survival.
.There is . . . “no justification for screening
programmes that expose men who might never be aware of the pathological changes within their prostates, to uncertainties about outcome and to
certainties about the disagreeable nature of the treatment process.” “Exposing
healthy people to treatments with specific hazards and uncertain benefits is
unacceptable”
“On the basis of the
evidence, national programs of prostate screening are not justified.” Screening
is a striking instance of therapeutic optimism.
4-3 SCREENING MEN FOR PROSTATE AND COLORECTAL
CANCER IN THE UNITED STATES.
Among
men in the USA, PC screening is more common than CRC screening. Men who choose
to be screened should be made aware of the known mortality benefit of CRC
screening, and the uncertain benefits of screening for prostate cancer.
Men who
insist on PSA screening should be informed of the greater benefit of
colonoscopy.
5-7 VARIATION
OF SERUM PROSTATE-SPECIFIC ANTIGEN
PSA may
fluctuate over short periods of time. A single elevated PSA should be viewed
with caution.
An
isolated elevation of PSA should be confirmed several weeks later before
proceeding with further testing, including biopsy.
6-14 NONINVASIVE DETECTION OF CLINICALLY OCCULT
LYMPH-NODE METASTASES IN PROSTATE CANCER.
High resolution MRI with magnetic iron-containing
nanoparticles allowed detection of small and otherwise undetectable lymph-node
in patients with metastatic PC.
7-12 THE INFLUENCE OF FINASTERIDE ON DEVELOPMENT
OF PROSTATE CANCER
Finasteride prevents or delays the appearance of PC at
a risk of increasing incidence of high grade cancers.
Not yet ready for general use, but provocative.
Preventive or delaying measures may be in the offing.
Once-daily fondaparinux without monitoring is at least as
effective and safe as adjusted-dose IV unfractionated heparin in the initial
treatment of hemodynamically stable patients with pulmonary embolism.
“Because
of its simplicity, once-daily subcutaneous fondaparinux without anticoagulation
monitoring could replace intravenous administration of unfractionated heparin
in most patients.”
Combined ACE-I and A II-I therapy safely
retarded progression of non-diabetic renal disease more effectively than either
drug alone.
REQUESTS FOR CLINICAL SERVICES
7-5 DIRECT OBSERVATION OF REQUESTS FOR CLINICAL SERVICES IN OFFICE
PRACTICE.
Patient-requests for prescriptions are becoming more frequent as
direct-to-the-public advertising by drug companies becomes more common.
Patient-requests for consultations, and tests are also becoming more frequent
as the public becomes more sophisticated.
Primary care clinicians will find it
necessary to negotiate with patients about these requests. Physicians’ role in
educating patients about risks, benefits, and costs of new “miracle” drugs is
becoming more important.
Primary care clinicians must increasingly understand patients’
anxieties and what they really want to receive from the
consultation.
The patient negotiates from fear and uncertainty. The physician negotiates from
a specialized knowledge. Meeting a common ground satisfactory to both requires
patience and give-and-take.
10-12 RESTLESS LEG SYNDROME SYMPTOMS IN PRIMARY
CARE.
Restless leg syndrome (RLS) is a sleep disorder that accounts
for a significant proportion of patients with sleep complaints.
Currently, to be considered positive for
RLS, four criteria must be met:
1. Urge to move the legs,
usually accompanied by an unpleasant sensation in the legs.
2. Symptoms must be aggravated
by rest.
3. Symptoms must be alleviated
by movement, in particular, walking.
4. Must be worse in the evening
or at night either currently or in the past when the condition
first started.
In this study, twenty four percent of patients were
positive for all 4 of the essential symptoms.; 15% reported
the
symptoms at least weekly. A large number of RLS patients may be seen by primary
care clinicians.
A variety of drugs has been recommended for treatment:
dopamine precursors (eg, levodopa; Laradopa),
dopamine
agonists (eg bromocriptine; Parlodel),
anticonvulsants, benzodiazepines, and even opioids.
The variety of drugs recommended for
treatment speaks for the lack of
studies to determine preference. Drug therapy in practice would likely be based
on trial and error. The FDA has not reviewed them for specific use in RLS.
2-6 ADDING A TEST FOR HUMAN PAPILLOMA VIRUS DNA
TO CERVICAL-CANCER SCREENING
Virtually all squamous-cell cervical
carcinomas contain one of eighteen types of human papilloma virus (HPV). The relative risk of cervical cancer
associated with persistent infection with high-risk types of HPV (especially
types 16 and 18) is higher than the risk of lung cancer associated with
smoking.
The discovery that continued presence of
tumor-producing HPV is necessary for development of cervical cancer is
revolutionizing our approaches to screening and prevention. An obvious
corrrelary is that the absence of infection means that the risk of cervical
cancer is negligible.
4-1 SCREENING FOR PROSTATE CANCER
“Few
issues are as controversial.” Adequate
evidence is absent.
An
approach that recommends men should be fully informed of risks and benefits of
screening and then asked to make up their own minds is disingenuous when it is
clearly difficult for specialists advisors to know the best approach. At
present patients are offered an “informed” choice. But, the most informed observer
can point only to uncertainty.
“Tests
have no meaning without clarity of purpose.”
The main aim of PC screening is not to detect cancerous tissue, but to
identify men who are asymptomatic and would otherwise die or be disadvantaged
by untreated PC in the future, perhaps in 10 to 15 years.
The weakness of the case for
generalized screening rests on the poorly defined nature of the group
identified for treatment. Current predictive values are poor. We still do not
understand the natural history of PC well enough to distinguish those in whom
disease is likely to progress from those whose pathology presents limited risk
in terms of function and survival.
.There is . . . “no justification for screening
programmes that expose men who might never be aware of the pathological changes within their prostates, to uncertainties about outcome and to
certainties about the disagreeable nature of the treatment process.” “Exposing
healthy people to treatments with specific hazards and uncertain benefits is
unacceptable”
“On the basis of the
evidence, national programs of prostate screening are not justified.” Screening
is a striking instance of therapeutic optimism.
4-3 SCREENING MEN FOR PROSTATE AND COLORECTAL
CANCER IN THE UNITED STATES.
Among
men in the USA, PC screening is more common than CRC screening. Men who choose
to be screened should be made aware of the known mortality benefit of CRC
screening, and the uncertain benefits of screening for prostate cancer.
Men who
insist on PSA screening should be informed of the greater benefit of
colonoscopy.
4-4 MAMMOGRAPHIC SCREENING FOR BREAST CANCER.
Eight trials have been published. In patients between
ages 50 and 69, all reports of studies comparing screening with no screening
showed protective effects of screening—a statistically significant 20 to 35
percent reduction in mortality from BC.
The downside: False positive results necessitate
further investigation. Nationally, an average of 11% of screening mammograms are read as abnormal. BC is subsequently
found in about 3% of these women ( 0.3% of all mammograms). Thus, a woman has
about a 10% chance of a false positive result with each mammogram. Because
women are screened repeatedly, the risk of a false positive increases over
time. One study estimated that, after 10 mammograms, about half of women age 40
to 64 will have had a false positive leading to needle biopsy or open biopsy in
about 20%. The malpractice climate in the USA may work to increase the numbers
of false positive reports.
Compared with annual screening, screening
performed once three years after the last negative test in women who previously
had 3 or more consecutive negative PAP tests, is associated with an average
excess risk of cervical cancer of approximately 3 in 100 000. If continued,
screening annually after 3 negative tests, would result in thousands and
thousands of additional PAP tests and colposcopic examinations to detect only
one additional case of cervical cancer.
The US Preventive Services Task Force
recently recommended screening be performed “at least every 3 years” rather
than every year. The American Cancer Society suggests lengthening the intervals
between screenings to as long as 3 years among women age 30 and over who
previously have had negative results on three or more consecutive cervical
cancer tests.
Given that half of all cases of cervical
cancer occur in women who have never been screened, screening all women at
least once would be expected to contribute more to decreasing mortality than
the continued annual testing. The focus should be on screening women who have
rarely or never undergone screening.
12-7 SCREENING FOR DEPRESSION IN PRIMARY CARE
WITH TWO VERBALLY ASKED QUESTIONS
The US Preventive Services Task Force endorsed
screening for depression, but did not recommend a specific tool. Many primary
care clinicians find screening questionnaires for depression too cumbersome and
time consuming for routine use.
This study used a simple screening tool of two
questions. If one or two were answered positively, the screen was considered
positive, and further questions were asked to determine if major depression was
present. (A composite interview--the “Gold Standard”)
The screening questions:
1) During the past month have you often been bothered by feeling
down, depressed, or hopeless?
2) During the past month have
you often been bothered by little interest or pleasure in doing things?
In the community setting, the two
verbally asked questions have a good sensitivity (97%)
and
reasonable specificity (67%) for screening for depression. If the screen was
negative (both questions answered negatively) major depression is almost surely
absent.
About 5 false positives would occur for
every true positive when asking the questions alone.
This is common in screening studies
which are in essence a diagnostic test performed in a low prevalence setting.
Further questions will be required to clarify presence or absence of
depression.
12-10 SCREENING VIRTUAL COLONOSCOPY—READY FOR
PRIME TIME?
A new virtual colonoscopy (VC) used a
multidirectional CT scanner providing a primary
3-dimentional
endoluminal display. It permitted
faster, higher-resolution imaging than previously obtainable. Residual fluid
and stool was tagged by contrast material. The imaging software digitally
removed all opacified fluid and stool from the colon by a process called
“electronic cleansing”.
The study subjects received the VC
followed by conventional colonoscopy for comparison:
Sensitivity of VC for detection of
adenomas vs traditional colonoscopy:
10 mm or larger was 92% vs 88%
8 mm or larger was 92% vs 89%
6 mm or larger was 86% vs 90%
The study suggests that VC can detect
polyps of 6 mm or larger as accurately as conventional colonoscopy in a
population with a low prevalence of colorectal neoplasia.
Decisions regarding the use of VC as a
first-line screening test will require more information about cost and
insurance coverage. “The performance of VC in this asymptomatic population is
impressive, with detection rates similar to those achieved by conventional
colonoscopy.” Only if the important questions about the appropriate size
threshold and the surveillance of smaller polyps can be resolved will VC be
ready for prime time.
The bugaboo is the need for follow-up conventional colonoscopy to
remove suspicious polyps.
Patients will be asking about this. Application in the local community
is likely to be far-off.
There are two basic human needs—health and autonomy.
Autonomy is closely linked with self esteem and the earning of respect. “Low
levels of autonomy and low self esteem are likely to be related to worse
health.” Increasing pride in one’s identity may have a more favorable effect on
health behaviors and risks than focusing on how to change the risks themselves.
There is a link between low self esteem and ill health. “All people have a
basic need for autonomy and self esteem.”
Primary care clinicians can enhance the self-esteem of
patients with low esteem by listening carefully to their problems and showing
respect and concern.
SENSITIVITY, SPECIFICITY, PREDICTIVE
VALUES, AND LIKELIHOOD RATIOS
12-8 REVIEW
OF SENSITIVITY, SPECIFICITY, PREDICTIVE VALUES AND LIKELIHOOD RATIOS
Calculate sensitivity from the left
column; specificity from the right column; positive predictive value from the
top row; negative prediction value from
the bottom row; the likelihood ratios from both columns.
See text.
7-4 MORTALITY RISK REDUCTION ASSOCIATED WITH
SMOKING CESSATION IN PATIENTS WITH CORONARY DISEASE.
Smoking cessation has a greater effect on reducing the risk of mortality
among patients who smoke than the effect of any other intervention. Risk of
death was reduced by 36% in those who
quit.
Ask your patients who smoke to read this article.
In
smokers with CAD who quit, risk of sudden cardiac death (SCD) is significantly reduced and compares with the risk of those who never
smoked. The decline in risk associated with cessation is immediate and not time
dependent. This supports the view that the risk is due to direct toxic effects.
The risk in smokers is not related to the amount of smoking.
In absolute terms, smoking cessation and never smoking
resulted in a 3.5% lower risk of SCD over 8 years
compared
with those who continued to smoke. [NNT(8 years to prevent one SCD) = 30]. And a 11% reduction in all-cause death. [NNT
= 10].
The risk of continuing smoking on SCD is even more
pronounced than other risk factors—age, sex,
New York
Heart Association functional class, BP, and dyslipidemia.
Cessation is certainly one of the most effective preventive
measures. Despite being informed of the risks, many patients continue to smoke.
Primary care clinicians who succeed in getting recalcitrant smokers to stop
achieve a major therapeutic intervention. Would asking them to read a copy of
this article help? RTJ
The hallmark of social anxiety disorder (SAD) is
extreme and persistent fear of embarrassment and humiliation. People with SAD
(also known as social phobia) avoid participating in social and public
activities such as public speaking, social gatherings, and meetings. The
intense symptoms of SAD interfere with functioning and cause marked distress.
It is the third most prevalent
psychiatric disorder in the USA. Paroxitine and sertraline are effective drug
therapy.
SAD can be differentiated from panic
disorder by its consistent relation to social issues.
Less severe, and more common symptoms can benefit from beta-blockers.
1-1 WHY DO GENERAL PRACTITIONERS PRESCRIBE
ANTIBIOTICS FOR SORE THROAT?
Describing the difference between
“Evidence Based Medicine” and the “Real World” of practice. Despite the power
of EBM, there are many instances and reasons for deviation.
7-13 INTERACTION OF SPIRINOLACTONE WITH ACE INHIBITORS
OR ANGIOTENSIN-RECEPTOR BLOCKERS
Spirinolactone
and ACE inhibitors act synergistically or additively to increase plasma
potassium levels. Toxic and even lethal concentrations may result.
Spirinolactone is established as an important additive in therapy for patients
with severe heart failure. The dose should not exceed 25 mg daily, and in some
patients should be less.
1-15 DRUG
ELUTING STENTS IN VASCULAR INTERVENTION
Immunosuppressive agents (which inhibit
tumor-cell growth) may also inhibit the benign tissue proliferation
characterizing intimal hyperplasia. Several immunosuppressants have been tested
for potential to inhibit restenosis. Stents coated with the agents are becoming
available. Local drug delivery achieves higher tissue concentrations of drugs,
while producing no systemic effects. This is associated with a marked reduction
in the risk of re-stenosis.
“The
clinical impact of the elimination of restenosis may influence the approach to
coronary artery disease, the future of cardiac surgery, and health-care
economics.”
9-14 EFFECT
OF ST JOHN’S WORT ON DRUG METABOLISM BY INDUCTION OF CYTOCHROME P450 3A4 ENZYME
Long-term dosing of St John’s wort results
in induction of the liver enzyme
cytochrome P450 3A4. This hastens metabolism of many drugs and diminishes their
plasma levels and clinical effectiveness. This leads to increased dosage
requirements of the 50% of drugs metabolized by this liver enzyme.
St. John’s wort can significantly alter
the effectiveness and dosing of a wide range of medications.
Patients’ use of
herbal nostrums continues undiminished.
“Natural” is considered harmless even by the most sophisticated
patients. This is another good reason
for primary care clinicians to insist that patients “brown bag” all medications
they take at each office visit.
7-1 DIAGNOSING STREP THROAT IN THE ADULT
PATIENT: DO CLINICAL CRITERIA REALLY
SUFFICE?
Recently the American College of Physicians
recommended an algorithm which may be used to diagnose group A strep
pharyngitis on clinical grounds alone, eschewing microbiological testing.
Tonsillar exudates
Tender anterior cervical
adenopathy
Fever
Absence of cough.
The ACP guidelines allow empirical
antibiotic treatment for patients who meet 3 or 4 of the criteria, and
non-treatment for all others.
Other prestigious organizations recommend rapid antigen testing or culture
before treatment is begun.
Most primary care clinicians would
likely chose to treat with penicillin on clinical grounds.
2-8 ALCOHOL
CONSUMPTION AND RISK OF STROKE: A
Meta-analysis
Heavy alcohol consumption increases risk of stroke.
Light-to-moderate consumption protects against ischemic stroke, but not against
hemorrhagic stroke.
In the elderly, vaccination against influenza was associated with large
reductions in numbers of hospitalizations from heart disease, cerebrovascular
disease, as well as pneumonia and influenza. Risk of death was reduced by about
50%.
Flu vaccination is one of the most
cost-effective health interventions. Primary care clinicians bear
responsibility for increasing uptake by the general population.
3-5 SILENT BRAIN INFARCTS AND THE RISK OF
DEMENTIA AND COGNITIVE DECLINE
Silent brain infarcts are common in the
elderly. Persons with silent brain infarcts had an increased risk of dementia,
and a steeper decline in cognitive function than persons without such lesions.
In clinical practice—How can we intervene to benefit
the patient? The hope is that treatment directed at vascular disease will
reduce the burden of dementia. We should optimize cardiovascular health by
established means: control of hypertension; lipid control; weight control; exercise;
smoking-avoidance.
Other possible beneficial interventions: low-dose
aspirin; one alcoholic drink
daily; and folic acid supplementation
to reduce homocysteine levels.
Stroke risk varies greatly in AF patients. This study
sought to derive and validate a simple and easily applied clinical rule to
identify individuals with non-valvular AF whose stroke risk while taking
aspirin is low enough that oral anticoagulation is not necessary.
Irrespective of age, a patient with non-valvular AF
without previous stroke or TIA, without hypertension, without symptomatic
coronary heart disease or heart failure, and without diabetes can take aspirin
for stroke prevention and would not likely benefit from anticoagulation.
Use of the rule would prevent almost one quarter of AF
patients, regardless of age, to avoid anticoagulation. Sixteen percent of patients over age 75 were
classified as low risk and thus would not be exposed to the risks of
anticoagulation.
In absolute terms, benefits were small, with absolute
differences between groups of 0.6% to 2.1%.
(NNT [to benefit one patient over 3 years] = 47 to 166.)
“Reaction to the 36% relative reduction in the primary
endpoint and the other benefits observed in ASCOT
may
need to be tempered by consideration of the absolute risk reduction of a
coronary event of 3.4 per 1000 patients-years.” “There are clearly financial implications.” (As well as adverse events from the drug. RTJ)
Stroke risk varies greatly in AF patients. This study
sought to derive and validate a simple and easily applied clinical rule to
identify individuals with non-valvular AF whose stroke risk while taking
aspirin is low enough that oral anticoagulation is not necessary.
Irrespective of age, a patient with non-valvular AF without
previous stroke or TIA, without hypertension, without symptomatic coronary
heart disease or heart failure, and without diabetes can take aspirin for
stroke prevention and would not likely benefit from anticoagulation.
Use of the rule would prevent almost one quarter of AF
patients, regardless of age, to avoid anticoagulation. Sixteen percent of patients over age 75 were
classified as low risk and thus would not be exposed to the risks of
anticoagulation.
6-17 ASPIRIN AND TICLOPIDINE FOR PREVENTION OF
RECURRENT STROKE IN BLACK
Ticlopidine was not more effective than aspirin in preventing recurrent stroke in
Afro-Americans. Aspirin is a better treatment than ticlopidine for aspirin-tolerant
Afro-Americans with noncardioembolic ischemic stroke.
This risk score for embolic stroke was derived from 5
risk predictors: advancing age, female
sex, increasing systolic BP, prior stroke or TIA, and diabetes. The score can
be used to estimate absolute risk of
stroke (5% to 75% over 5 years) and help to negotiate treatment decisions with
patients with AF at the time they are first diagnosed. . Risk may be stratified into mild, moderate
or severe.
Although some physicians and patients may more readily
accept and act on a numerical risk prediction,
I
believe primary care clinicians can just as accurately judge risk without
creating a numerical 5-year “risk”. Most patients will eventually end up
receiving anticoagulation. It is nevertheless important to spare those at low
risk from the potential adverse effects of warfarin therapy and use aspirin
instead. Patients with AF, but without structural heart disease, (including no
hypertension) are at relatively low risk, especially if they are under age 65.
To anticoagualate or not anticoagualate is a difficult
and important decision. It remains a clinical-judgment call. For each patient,
clinicians must strike an acceptable balance between risk of ischemic stroke
and bleeding. In the absence of an absolute or important relative
contraindication, the data seem compelling that warfarin therapy should be
offered to most patients with AF. The difficulty is to know what threshold of
stroke risk is low enough so that the potential risk of warfarin therapy
outweighs its potential benefits. For
most patients the potential benefits of stroke prevention will outweigh the
potential risks of bleeding secondary to warfarin.
An article (Annals
Internal Medicine April 28 , 2003; 163: 936-43; Practical Pointers April 2003) differs somewhat in suggesting that up to
1/3 of patients with AF can be classified as low-risk and treated with aspirin.
Emboli of atrial origin are larger than
average. The brain infarcts they
produce are more disabling and lethal.
Among patients with non-valvular AF, the degree of
anticoagulation at admission for stroke was associated with risk of disability and death.
Anticoagulation that resulted in an INR of 2.0 or greater reduced frequency and
severity of ischemic stroke and risk of death. This is evidence against INR
targets below 2.0
Risk of hemorrhagic stroke did not
increase until INR was 4.0 or above.
INR below 2.0 and aspirin protect against stroke less
effectively than INR 2.0 to 3.0, but
are superior to use of no anticoagulant. Aspirin is adequate prophylaxis
in patients considered at low risk for thromboembolic stroke. Eventually almost
all patients with AF will become high risk due to age and co-morbidity. As age
progresses, risk of bleeding from warfarin increases. This dilemma must be
solved on an individual basis. Patients accepting warfarin must be carefully
controlled at a stable INR around 2.5.
“Our results
provide further support for anticoagulation to achieve an INR of 2.0 or greater
(eg, 2.5) in patients with non-valvular atrial fibrillation.”
Ximelagatran is a direct thrombin inhibitor which is
given orally.. Its pharmacokinetic profile is predictable and stable overtime.
It has low potential for drug-drug interactions and does not require monitoring
or dose adjustment.
Fixed dose ximelagatran was at least as effective as
well-controlled warfarin for prevention of
stroke and systemic embolism. It is much easier to use.
Practical Pointers has abstracted several articles on
the new oral anticoagulant ximelagatran. (See October 2003 issue.)
Ximelagatran looks very promising.
SUDDEN ACUTE RESPIRATORY SYNDROME (SARS)
3-6 SUDDEN ACUTE RESPIRATORY SYNDROME (SARS)
“Plagues are as certain as death and taxes. The
optimism of the 1960s and 1970s has given way to a mature realism that
relationship between human beings and microbes is neither completely
predictable nor biased in favor of humans.” Is SARS a rehearsal for the next
pandemic of influenza.?
The disease represents a sudden jump from animal
species to humans. The virus probably evolved in animals for eons and for some
reason suddenly became able to infect humans.
The SARS story has been astounding! In a short period of 2 months, the
world-wide epidemiology has been described, the virus identified, its genetic
code determined, and control measures instituted and found effective. As of the
end of April 2003, the epidemic has been declared to be controlled in Vietnam
and in Toronto Canada because no new cases were reported over a 3 week period.
How would the history of the 20th century have changed if we had the
technology, control measures, and world-wide instantaneous communication
available during the 1918 influenza epidemic?
The ability of the virus to spread and cause serious
illness and death in healthy persons increases the alarm.
Is
SARS a rehearsal for the next pandemic of influenza.?
7-2 ACUTE UNCOMPLICATED URINARY TRACT INFECTION
IN WOMEN.
Trimethoprim-sulfamethoxazole (TM-S) for 3 days remains the therapy of
choice. Telephone consultation and treatment is safe.
For
recurrent episodes of infection and for prophylaxis, self treatment is a
reasonable clinical approach.
5-12
PACEMAKER THERAPY FOR PREVENTION OF SYNCOPE IN PATIENTS WITH RECURRENT
SEVERE VASOVAGAL SYNCOPE
Pacing therapy did not significantly reduce the risk
of recurrent syncope in patients with vasovagal syncope.
Long-term, low-intensity warfarin therapy with a
target INR of 1.5 to 2.0 was highly effective in preventing recurrent VTE in
patients with a history of idiopathic
VTE, including patients with thrombophilia due to factor V Leiden and
prothrombin mutations.
For patients with acute VTE, low-dose warfarin is
appropriate after a 3-month course of conventional-dose warfarin. How long
should therapy be continued? No definite answer, but probably long-term.
Oral, but not transdermal ERT, was
associated with risk of VTE in postmenopausal women. Transdermal administration
avoids the first pass through the liver and blunts production of thrombogenic
proteins by the liver.
A good example of the advantages of
transdermal application of drugs.
“The intensity of anticoagulation for patients who
have had unprovoked venous thromboembolism should not be reduced after the
first three months of treatment.” Such a reduction increases risk of
recurrence. INR should remain at 2.0 to 3.0.
Risk of recurrent VTE was 0.7 per 100 patient-years in
the INR 2.0 to 3.0 group vs 2.8 per 100 patient years in the INR 1.5 to 1.9
group.
In this study, there was no evidence that aiming for
an INT of 1.5 to 1.9 (vs 2.0 to 3.0) reduced risk of bleeding.
I believe that in the “real world” of primary care,
aiming for a higher INR will be related to an increased risk of bleeding.
Indeed, bleeding risk is increased in patients who aim for the lower INR as
compared with placebo.
An article in NEJM
April 10, 2003; 348; 1425-34 reported that a low-level INR (target 1.5 to
2.0; compared with placebo) in patients with unprovoked VTE was highly
effective in preventing recurrence. It is likely that a higher target will be
slightly more effective in prevention, but will lead to greater risk of
bleeding. Again a clinical judgment call based on individual-patient
characteristics and preferences.
After 3-months of anticoagulation for a first episode
of unprovoked VTE, measuring D-dimer levels allowed identification of a subset
of patients with very low risk of recurrence. Patients with a level of less
than 250 ng/mL 3 weeks after discontinuation of oral anticoagulation were at
low risk.
The cumulative probability of recurrent VTE at 2 years
among those with levels < 250 was 3.7%.
Among those with higher levels was 11.5%
A higher D-dimer is likely to be related to ongoing
thrombosis-thrombolysis due to a thrombogenic potential.
10-2 TREATING THROMBOSIS IN THE 21ST
CENTURY
Now, a minimal anti-thrombin-binding unit of heparin, a
pentasaccharide called fondaparinux, has been synthesized and is undergoing
clinical trials. Fondaparinux enhances anti-thrombin activity. It is a specific
inhibitor of activated factor X (Xa). It requires subcutaneous administration.
It can be given once a day on a weight basis. It does not require laboratory
monitoring.
A second new anticoagulant (melagatran)
took its cue from the leach which produces a direct thrombin inhibitor
(hirudin). Hirudin acts independently
of anti-thrombin and other plasma proteins. The discovery of hirudin led to
other direct thrombin inhibitors, one of which is melagatran. Melagatran can
also neutralize clot-bound thrombin. Chemical modification (to “ximelagatran”)
allows better oral absorption. It is the first new oral anticoagulant since
warfarin. Like fondaparinux, it does not require laboratory monitoring.
Fixed dose ximelagatran 36 mg bid, administered without
coagulation monitoring, was significantly more effective than warfarin in
prevention of thromboembolism after knee replacement. Safety was similar “It could therefore be considered an
alternative to other thromboprophylactic agents.”
10-5 SECONDARY PREVENTION OF VENOUS
THROMBOEMBOLISM WITH ORAL DIRECT THROMBIN INHIBITOR XIMELAGATRAN
Ximelagatran is a direct thrombin
inhibitor undergoing active investigation as an anticoagulant. It is given in a
fixed dose daily, and needs no monitoring.
Beginning and continuing extended secondary prevention of
VTE with ximelagatran 24 mg bid for an additional 18 months after 6 months of
standard anticoagulation effectively prevented recurrences. [NNT = 10]
The incidence of major hemorrhage was low and similar to
placebo. Ximelagatran was equally
effective in subgroups that had risk factors for recurrence—previous VTE,
proximal deep VTE, and pulmonary embolism.
The fixed-dose ximelagatran was well
tolerated without monitoring measures of coagulation.
In patients with venous thromboembolism (VTE), there is a perception that the clinical impact of
preventing recurrent VTE and possible fatal pulmonary embolism outweighs the
risk of bleeding associated with long-term anticoagulation..
The subgroup of patients with idiopathic
(unprovoked) VTE, and VTE associated with factor V Leiden, prothrombin
mutations, and deficiencies of protein C and protein S make up about half of
the thousands of patients in whom symptomatic VTE is diagnosed each year in the
USA.
The optimal duration of anticoagulation
is still unclear.
This systematic review of randomized,
controlled trials and prospective cohort studies
(10
757 patients; 4373 patient-years) investigated patients with confirmed
idiopathic VTE. All received oral anticoagulant therapy (target INR--2.0 to
3.0) for at least 3 months. Nine of 33 studies reported use for over 3 months
(6 to 24 months).
The chances of a major bleed per year of anticoagulation were 7 in
100 patients with 1 in 1000 chance of fatality, and about 1 chance in 100 of an
intracranial bleed.
The primary care clinician must make
some attempt to balance the risk of bleeding vs the benefits of
anticoagulation
in each individual patient. (I know of no
means of doing this beyond “clinical judgment”. RTJ )
4-12
EFFECT OF MULTIVITAMIN AND MINERAL SUPPLEMENT ON INFECTION AND QUALITY OF LIFE
A daily multivitamin-mineral supplement was associated
with reduced incidence of patient-reported infection and related absenteeism in
the subset of patients with type 2 diabetes who had a high prevalence of
subclinical micronutrient deficiency.
6-11 USE OF ANTIOXIDANT VITAMINS FOR THE
PREVENTION OF CARDIOVASCULAR DISEASE
A lack of beneficial effect was seen consistently for
various doses of these two vitamins in diverse populations. The routine use of
vitamin E is not supported. The use of beta carotene is associated with a small
but significant excess of all-cause mortality and cardiovascular death.
Vitamin D supplements of 100 000 IU given orally every
4 months for primary prevention was
associated with a lower risk of fractures (and without adverse effects) in
older men and women living in the community.
This is equivalent to our usual dose of 800 IU daily.
Calcium supplements would have lowered risk even more.
Long-term, low-intensity warfarin therapy with a
target INR of 1.5 to 2.0 was highly effective in preventing recurrent VTE in
patients with a history of idiopathic
VTE, including patients with thrombophilia due to factor V Leiden and
prothrombin mutations.
For patients with acute VTE, low-dose warfarin is
appropriate after a 3-month course of conventional-dose warfarin. How long
should therapy be continued? No definite answer, but probably long-term.
“The intensity of anticoagulation for patients who
have had unprovoked venous thromboembolism should not be reduced after the
first three months of treatment.” Such a reduction increases risk of
recurrence. INR should remain at 2.0 to 3.0.
Risk of recurrent VTE was 0.7 per 100 patient-years in
the INR 2.0 to 3.0 group vs 2.8 per 100 patient years in the INR 1.5 to 1.9
group.
In this study, there was no evidence that aiming for
an INT of 1.5 to 1.9 (vs 2.0 to 3.0) reduced risk of bleeding.
I believe that in the “real world” of primary care,
aiming for a higher INR will be related to an increased risk of bleeding.
Indeed, bleeding risk is increased in patients who aim for the lower INR as
compared with placebo.
An article in NEJM
April 10, 2003; 348; 1425-34 reported that a low-level INR (target 1.5 to
2.0; compared with placebo) in patients with unprovoked VTE was highly
effective in preventing recurrence. It is likely that a higher target will be
slightly more effective in prevention, but will lead to greater risk of
bleeding. Again a clinical judgment call based on individual-patient
characteristics and preferences.
Fixed dose ximelagatran 36 mg bid, administered without
coagulation monitoring, was significantly more effective than warfarin in
prevention of thromboembolism after knee replacement. Safety was similar “It could therefore be considered an
alternative to other thromboprophylactic agents.”
Ximelagatran is a direct thrombin inhibitor which is
given orally.. Its pharmacokinetic profile is predictable and stable overtime.
It has low potential for drug-drug interactions and does not require monitoring
or dose adjustment.
Fixed dose ximelagatran was at least as effective as
well-controlled warfarin for prevention of
stroke and systemic embolism. It is much easier to use.
Practical Pointers has abstracted several articles on
the new oral anticoagulant ximelagatran. (See October 2003 issue.)
Ximelagatran looks very promising.
10-17 THE GREATEST THREAT TO WOMEN’S HEALTH
Heart attacks and stroke kill twice as many women as all
cancers combined. Moreover, contrary to conventional wisdom, women are more
likely to die from cardiovascular disease than men.
Getting women to stop smoking, eat healthily, drink alcohol
only in moderation, lose weight if appropriate, and take regular exercise
involves changing behaviors that are often ingrained from childhood.
More
than half of all deaths and disability from heart disease and stroke can be
prevented.
“Advising women, as well as men, about their risks of
cardiovascular disease should, we urge, be mandatory for all primary care
practitioners.”
9-2 ORAL XIMELAGATRAN FOR SECONDARY PROPHYLAXIS
AFTER MYOCARDIAL INFARCTION
In patients with a recent MI, long term treatment with
ximelagatran, combined with aspirin, was more effective than aspirin alone in
reducing frequency of major cardiovascular events. [NNT (for 6 months to benefit one) = 33]
Ximelagatran is the first of a
new class of oral direct-thrombin
inhibitors under investigation. It is rapidly metabolized to its active
form, melagatran. It is stable over time. Its metabolism is unaffected by age,
sex, body weight, or ethnic origin. It is not affected by the hepatic cytochrome
P450 enzyme system, thus providing a low potential for drug-drug
interactions. There are no relevant
food or alcohol interactions.
“Melagatran’s pharmacokinetics are unchanged and the pharmacodynamic
properties show only minor additive effects when oral ximelagatran and
acetylsalicylic acid are given concomitantly.”
Ximelagatran has undergone extensive assessment in
patients with venous thromboembolism and atrial fibrillation. It has a rapid
onset of action, achieves a peak level within 2 hours, and has a half-life of 4
hours. It is administered twice daily. There is no need of monitoring and dose adjustments. (Monitoring of liver and kidney
function is required. RTJ)
Ximelagatran is primarily excreted by the kidney. Data on patients with
kidney dysfunction are limited.
With the 24 mg BID dose, the bleeding rate was low,
and high concentrations of alanine amino transferase occurred less frequently
(7%).
“It is good news that the more than half
century wait of new and improved oral antithrombotics finally appears to be
ending.”
Fixed dose ximelagatran 36 mg bid, administered without
coagulation monitoring, was significantly more effective than warfarin in
prevention of thromboembolism after knee replacement. Safety was similar “It could therefore be considered an
alternative to other thromboprophylactic agents.”
10-5 SECONDARY PREVENTION OF VENOUS
THROMBOEMBOLISM WITH ORAL DIRECT THROMBIN INHIBITOR XIMELAGATRAN
Ximelagatran is a direct thrombin
inhibitor undergoing active investigation as an anticoagulant. It is given in a
fixed dose daily, and needs no monitoring.
Beginning and continuing extended secondary prevention of
VTE with ximelagatran 24 mg bid for an additional 18 months after 6 months of
standard anticoagulation effectively prevented recurrences. [NNT = 10]
The incidence of major hemorrhage was low and similar to
placebo. Ximelagatran was equally
effective in subgroups that had risk factors for recurrence—previous VTE,
proximal deep VTE, and pulmonary embolism.
The fixed-dose ximelagatran was well
tolerated without monitoring measures of coagulation.
Ximelagatran is a direct thrombin inhibitor which is
given orally.. Its pharmacokinetic profile is predictable and stable overtime.
It has low potential for drug-drug interactions and does not require monitoring
or dose adjustment.
Fixed dose ximelagatran was at least as effective as
well-controlled warfarin for prevention of
stroke and systemic embolism. It is much easier to use.
Practical Pointers has abstracted several articles on
the new oral anticoagulant ximelagatran. (See October 2003 issue.)
Ximelagatran looks very promising.