PRACTICAL POINTS FOR PRACTICE
MEDICAL SUBJECT HEADINGS
HIGHLIGHTS AND EDITORIAL COMMENTS
This document is divided into three parts:
1) “Practical
Points”—one sentence statements of how the articles abstracted during the 6
months may influence primary care practice.
2) Seventy seven medical subject headings (MeSH) from “Absolute
Cardiovascular Risks” to “Ximelagatran”. Each of the medical subject headings is linked
to one or more
“Highlights and Editorial
Comments” of articles abstracted during the first half of 2005.
3) A “Highlights-Editorial
Comments” Section, arranged alphabetically following the list of MESH, provides a means of recalling to memory, in an
evening or two, what the editor considered
new and important for primary care presented in 6 flagship journals over the 6 months.
The numbers in the brackets refer to the full abstract. For example, [6-2] indicates the 2nd abstract
published in the June issue.
The indexes and each monthly issue for the past 5 years can be found on
the website (www.practicalpointers.org). HTML links make possible easy and speedy
access to the full abstract and the journal reference of all articles abstracted
under an individual MeSH.
I hope you find the publication useful and interesting.
Richard T. James Jr.
M.D.
The editor thanks Whitney Lowell for internet applications and Lois M.
James for proofreading.
PRACTICAL POINTS JANUARY-JUNE 2005
HOW THE ARTICLES ABSTRACTED INFLUENCED MY PRACTICE
·
Consider use of herpes zoster vaccine
when it becomes available. [6-1]
·
Consider use of delayed prescriptions
for acute lower respiratory infections [6-2]
·
Encourage patients to consider their abdominal
girth a risk factor [6-3]
·
Be cautious in using aspirin for
primary protection of CHD in elderly women. [6-5]
·
Care in using antipsychotic drugs in
nursing homes [6-6]
·
Consider a thiazide a first-line treatment in hypertensive
diabetics and blacks [6-8] [4-1]
·
Use opioids
more freely for patients with neuropathic pain [6-9] Consider use of gabapentin combined with
morphine for severe neuropathic pain [3-4]
·
Advise patients that high dose
vitamin E is useless in the elderly with memory defects or for reduction of
risk of cardiovascular disease and cancer. And it may be toxic [6-10] [3-10]
·
Advise younger overweight patients
that weight loss will prevent later development of hypertension [6-11]
·
Continue to advise vitamin D (800 IU)
for primary prevention of osteoporosis and fractures [5-3]
·
For first-line therapy, advise
symptomatic treatment for traveler’s diarrhea, not antibiotics. [5-4]
·
For patients with persistent cough,
pertussis is a possibility [5-5]
·
Oral vitamin B12 in high dose is
effective therapy [5-6]
·
Progesterone, not estrogen, is the
risk factor for breast cancer in women receiving HRT [5-7]
·
Inform men about risks of PSA
screening as well as benefits. Consider that “most prostate cancers now removed
need not be removed” [5-9]
·
Treat acute pain of herpes zoster aggressively to lower
severity of post-herpetic neuralgia pain [5-10]
·
Stress the benefits of a modified Mediterranean
diet which contains poly-unsaturated fats as well as mono-unsaturated fats. [4-4]
·
Consider the “Money needed to treat”
as well as the “Number needed to treat needlessly” [4-6]
·
Consult with your cardiologist
consultants about availability and advisability of cardiac resynchronization in
patients with left bundle-branch-block and heart failure. [4-10]
·
Consider myasthenia gravis in a
patient with fluctuating weakness which improves with rest and application of
cold. [4-11]
·
Consider that all adults have at
least one risk factor for cardiovascular disease. All should be considered in
each individual patient. Changing life-styles is basic therapy. Many will benefit
from drug therapy [3-1] [3-2]
·
Know the drugs available for
prophylaxis and treatment of influenza [ 2-1]
·
Never give up encouraging smokers to
quit [ 2-3]
·
For atrial
fibrillation, rate control is preferable to rhythm control [ 2-4]
·
Simple first aid and local wound care
the best approach for bites of the brown recluse spider. [ 2-6]
·
Extent of treatment of hypertension
and dyslipidemia should depend on the patient’s absolute cardiovascular risk. [1-1]
·
In considering application of results
of trials beware of surrogate endpoints, composite outcome measures,
underreporting of adverse effects, and reports by pharmaceutical companies. [1-2]
·
Uncertainty is inherent in primary
care practice. Evidence helps quantify the uncertainty, but cannot remove
it. [1-4]
·
Know the benefits of a new class of
drugs to treat breast cancer (aromatase inhibitors) [1-5]
·
Fast foods are an ominous public
health issue [1-8]
·
For patients with persistent
dyspepsia consider testing of H pylori and treating if positive. [1-9]
·
The U. S Preventive Services Task
Force recommends one-time screening for abdominal aortic aneurysm in persons
who smoke. [1-11]
MEDICAL SUBJECT HEADINGS (MeSH) JANUARY-
JUNE 2005
ALLHAT STUDIES (SEE HYPERTENSION [6-8])
AROMATASE INHIBITOR (SEE BREAST
CANCER [1-5])
CONGESTIVE HEART
FAILURE (SEE HEART
FAILURE)
CORONARY
HEART DISEASE (SEE ALSO ISCHEMIC HEART DISEASE [5-2])
C-REACTIVE PROTEIN (SEE STATIN
DRUGS [1-13])
ESTROGEN (SEE HORMONE REPLACEMENT THERAPY)
FOLIC ACID (See HOMOCYSTEINE [3-9])
FRACTURE (SEE VITAMIN D [5-3])
GASTRO
ESOPHAGEAL REFLUX DISEASE
NUMBERS
NEEDED TO TREAT (NEEDLESSLY)
PAIN (SEE OPIOID AGONISTS [6-9])
PERTUSSIS (SEE WHOOPING COUGH
[5-5])
POLYPILL (SEE CORONARY HEART DISEASE)
POSTHERPETIC NEURALGIA
AND PAIN (SEE HERPES
ZOSTER)
POWER AND AUTHORITY IN MEDICINE
SENSITIVITY,
SPECIFICITY, AND PREDICTIVE VALUES: A REVIEW
HIGHLIGHTS AND EDITORIAL COMMENTS
JANUARY- JUNE 2005
Treat the Patient, Not the BP, Not
the cholesterol
Absolute risk of a cardiovascular
disease is the probability that an individual
patient will have an event over a defined period. It is determined by a
synergistic effect of all CVD risk
factors present in the individual. It may be true that, in a large group of
individuals with a systolic BP of 160, the CVD risk is twice as high as in a large group with a
systolic of 110 (relative risk). In
an individual, however, absolute risk depends on much more than a single risk
factor. Indeed, absolute differences in risk can vary more than 20-fold in
patients with the same BP.
“Cardiovascular
treatment benefit is directly proportional to the pre-treatment absolute risk.”
A
new approach to preventive therapy is to modestly reduce all modifiable risk
factors rather than concentrating on reaching “target levels’ of one or two.
This is a sea change in our approach to
lowering risk.
Please read the full
abstract.
Proposing an ABCDE Memory Device to Simplify Adherence to
Guidelines
1-6 A SIMPLIFIED APPROACH TO THE MANAGEMENT OF
NON-ST-SEGMENT ELEVATION ACUTE CORONARY SYNDROMES
The
study assembled a comprehensive plan through an “ABCDE” approach. The intention
was to provide a
memory device to overview therapies and
lifestyle changes that are clinically useful for patients with NSTE-ACS.
Elements
of the plan:
A Antiplatelets; Anticoagulation; ACE
inhibitors; Angiotensin II blockers.
B Beta-blockers; Blood pressure control
C Cholesterol management; Cigarette cessation
D Diet; Diabetes management
E Exercise.
This practical
approach allows physicians to more effectively create disease management
protocols, define roles and responsibilities for different medical personnel,
and ensure implementation of evidence-based short-
and long-term medical and risk-reducing
strategies.
This
plan is almost identical to a check list presented in the Archives Int Med July
2004 for secondary prevention of cardiovascular disease. (See Practical
Pointers July 2004 [7-8] )
I
believe check lists can be a valuable addition to primary care. In the hurried
pace of practice, we all omit (simply forget to consider) aspects of treatment
and lifestyle which should be addressed at almost every patient visit. A
mneumonic check list is a practical approach.
Some
clinicians may make their own. I tried to create a mneumonic check list for
diabetes:
D Diet;
Depression
I Insulin
A Aspirin; ACE
inhibitors
B BMI; BP
E Exercise
T Tests (blood glucose; HbA1c; lipids;
microalbuminuria; liver function; ejection fraction)
E Eye (retinopathy); Extremities (foot
health; foot pulses; peripheral neuropathy)
S Sulfonylureas, Statins, and other oral
drugs; Smoking
Plus
(Add others which might be indicated.)
“Ask Your Doctor if X is Right for You”
4-12 DIRECT-TO-CONSUMER ADVERTISING
A Haphazard Approach to Health
Promotion
DTCA drives sales of newer, more
expensive products for symptomatic relief of chronic conditions. The market
potential is huge. Erectile dysfunction, arthritis, and allergies are the most
common conditions advertised.
“Relying
on emotional appeals, most advertisements provide a minimal amount of health
information, describe benefits in vague, qualitative terms, and rarely offer
evidence of support claims.”
The
great majority of physicians believe that DTCA does not provide balanced
information. The FDA
rarely writes regulatory letters. “Millions of patients are
exposed to misleading advertisements.” Nearly 80% of physicians think that DTCA
encourages patients to seek treatments they do not need. Less than 10% of
physicians consider DTCA a positive trend in health care.
Is ED a manufactured “disease”? Is drug treatment mainly recreational?
I confess that
advertisements on TV touting a drug in market terms and then asking the
listener to “Ask your doctor if the drug is right for you” irritates me. It
would require considerable time and patience to educate individual patients
about the benefit/harm-cost ratio of a given drug. It may be easier to submit
as gracefully as possible.
I believe claims by drug
companies that DTCA is for instruction and benefit of the consumer are
specious. The purpose is to market the drug and increase profits.. After all, we live in a capitalistic society.
One or Two Drinks per Day may Reduce
Risk of Cognitive Decline
1-12 EFFECTS OF MODERATE
ALCOHOL CONSUMPTION ON COGNITIVE FUNCTION IN WOMEN.
This
study asks—What is the effect of moderate consumption of alcohol on cognition? A benefit is
plausible considering the strong link between moderate alcohol and decreased
risk of cardiovascular disease. Cognitive impairment and cardiovascular disease
share common risk factors.
Compared
with abstainers, moderate drinkers (less than 15 g alcohol per day; one drink)
had better mean cognitive scores. (Relative risk of impairment = 0.81 based on
a global cognitive score.) Also,
compared with abstainers, moderate drinkers (15 to 30 g per day) had a reduced
relative risk of cognitive impairment (although slightly less favorable, with
wider confidence intervals).
In
older women consumption of one alcoholic drink per day did not impair cognitive
function, and may actually decrease risk of cognitive decline.
Benefits of moderate alcohol consumption have
been reported with remarkable consistency over the past 10 years. Indeed, some
epidemiologists consider abstinence to be a risk factor for cardiovascular
disease.
As always, we should be cautious about generalizing the conclusions of
observational studies.
“Almost No Pattern of Drinking (Even
Low-To-Moderate) is Entirely Risk Free.”
Over the past 30
years, advances in our understanding of drinking problems have been
substantial.
This review
considers 3 subtopics: 1) the
epidemiology of alcohol’s role in health and illness, 2) treatment of alcohol
use disorders as part of public health, and 3) prevention and policy research.
Alcohol is
causally linked to more than 60 different medical conditions—most, but not all,
detrimental.
For most diseases there is a dose-response relationship. Not
only the volume of consumption, but patterns of drinking (especially binge
drinking) determine the burden of disease. Almost no pattern of drinking (even
low-to-moderate) is entirely risk free.
Breast cancer (BC):
Meta-analyses have shown
a linear increase in risk of BC associated with increasing average consumption
of alcohol.
Coronary heart disease
(CHD):
Comprehensive
meta-analyses reiterate the protective effect of low-to-moderate alcohol
intake—a J-shaped
curve.
Injury
(violence)
Several
pharmacological effects are likely to increase probability of aggressive
behavior.
Alcohol accounts
for about as much of the burden of disease globally as tobacco. Its burden is surpassed only by unsafe sex,
high blood pressure, and malnutrition.
Among heavy
drinkers who have no evidence of severe alcohol dependence, an intervention in
primary care aimed at reduction of drinking to moderate levels may benefit.
Evidence suggests that clinically significant effects on drinking behavior can
follow a brief intervention—but not in alcohol-dependent persons.
Overall, a discouraging
report. Primary care
clinicians may have some place in prevention of alcohol dependence by early
assessment and intervention.
Many
experts have urged screening, especially for patients who are hospitalized for
any reason.
AUDIT and CAGE questionnaires available on Google. Screening
in itself may broach the subject and lead patients to self-examination.
The
relation between breast cancer and alcohol has not been well publicized. I
believe it prudent to inform women at high risk (family history; breast cancer
genes) about the risk.
No
level of alcohol consumption is known to be safe in pregnancy.
Associated With A Slight Reduction
In Days Of Heavy Drinking
4-13 EFFICACY AND TOLERABILITY OF LONG-ACTING
INJECTABLE NALTREXONE FOR ALCOHOL DEPENDENCE
The opioid antagonist naltrexone has been shown to be effective
for treatment of alcohol dependence (AD).
The FDA approved naltrexone in 1994 to treat AD after it was shown to reduce
drinking frequency and likelihood of relapse to heavy drinking.
However, adherence to daily oral
therapy is problematic, as it is with other medications.
Recently a new
formulation of naltrexone has been made available. When given by injection, it
releases the drug over a period of one month without daily peaks in
concentration.
A randomized,
double-blind, placebo-controlled multicenter trial followed over 400 patients
(mean age = 45). All were considered to be AD and almost all were still
actively drinking (median heavy drinking days per month = 20). All were seeking
treatment for their AD.
Randomized to: 1) monthly injections of 380 mg long-acting
naltrexone, or 2) placebo injections.
All also received low-intensity psychosocial intervention.
Follow-up = 6
months.
Conclusion: Long-acting naltrexone, given by injection
once a month, was associated with a slight reduction in days of heavy drinking.
Authors
(with concurrence from journal editors) persist in reporting efficacy as
percentages. (“Naltrexone resulted in a 25% reduction in the event rate of
heavy drinking days”).
Results of the trial were not impressive. Dropout rate was high. Women
did not benefit. Adverse effects were frequent. “Spin” was evident.
The
most evident benefit shown by the study was in the “placebo” group (motivated
patients who received counseling). At 6
months there was a median reduction in days of heavy drinking per month from
about 19 to about 6. Naltrexone was
associated with a further reduction from
Should
primary care clinicians administer long-acting naltrexone by injection? I believe only in exceptional circumstances.
If a patient with AD approaches the primary care clinician for help, the desire
to quit must be understood to be strongly motivated. The clinician must be able
to provide adequate counseling. Follow-up must be rigid. The clinician and
patient must enter a contract to guide compliance. The small added benefit from
naltrexone must be made clear.
We await better treatments, perhaps with the addition of two or more
pharmacological agents (eg, acamprosate).
The
study was sponsored by Alkermes and Pharmacological Product Development Inc.
who collected and monitored the data. Data were managed and analyzed by Alkermes
clinical and statistical staff.
The USPSTF Now Recommends One-Time
Screening in Select Subsets of Men
1-11 SCREENING FOR ABDOMINAL ANEURYSM
The
U.S. Preventive Services Task Force (USPSTF)
now recommends one-time ultrasonographic screening for abdominal aortic
aneurysm (AAA) for men ages 65 to 75
who presently smoke or who have smoked in the past.
The
task force makes no recommendation for or against screening men who have never
smoked. It recommends against routine
screening for women.
One-time
screening is sufficient.
Is there any medical treatment? Will
beta-blockers decrease the rate of expansion by reducing the
stress caused by the steep increase in wall
expansion during systole? Many patients
in this age group with AAAs would be candidates for beta-blocker therapy
because of an increase in risk factors for CVD, including sub-optimal BP
control.
As always, primary care
clinicians must judge benefits vs harms of individual patients. The
availability of expert, safe surgery is a major factor influencing the
recommendation.
Advice for screening carries
ethical considerations. Although opportunistic preventive medicine is
considered a part of good medical practice, is it always ethically justifiable?
Consider a male smoker age 70 who consults for arthritis. Should the primary
care clinician at the time of the consultation advise the patient to undergo
screening for AAA? Should the primary care clinician advise a prostate specific
antigen?
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.
Every test carries a chance of a false-positive result leading to interventions
that do not benefit the patient, and may cause harm.
I believe many primary care
clinicians would limit screening for AAA to patients who consult for a specific
indication—assessment of their general health status.
Antibiotics Provided Little Advantage Compared With
No-Antibiotics.
6-2 INFORMATION LEAFLET AND ANTIBIOTIC
PRESCRIBING STRATEGIES FOR ACUTE LOWER RESPIRATORY INFECTION
Pharyngitis and acute bronchitis are the main causes of
excess antibiotic prescribing.
This pragmatic
study assessed the effectiveness of 3 different antibiotic strategies for acute
bronchitis.
Randomized,
controlled trial followed over 800 patients presenting to primary care with
acute uncomplicated
LRI.
Patients with findings suggestive of pneumonia were excluded—new focal
chest signs (focal crepitations or bronchial breathing); and systemic features (high fever,
vomiting, severe diarrhea). Also excluded patients with
asthma, other chronic or acute lung diseases, cardiovascular disease, or with
previous pneumonia.
Randomized
to: 1) no antibiotic prescribed [control
group], 2) delayed prescription [to be
picked up later], or 3) immediately prescribed antibiotic. The antibiotic of
choice was amoxicillin 250 mg 3 times daily for 10 days, or, if allergic,
erythromycin 250 mg 4 times a day for 10 days.
Compared with no
antibiotics [control group], the other strategies did not significantly alter
cough
duration: Delayed prescription shortened
duration by 0.75 days; immediate
prescription by 0.11 days. Treatment
group had no effect on duration of other symptoms.
“Compared with
immediate antibiotics, a strategy of either no offer of antibiotics or a
delayed prescription was associated with little difference in duration or
severity of symptoms.”
Overall, antibiotics probably do provide modest symptomatic relief. If a
benefit is present, it represents a shortening of only one day in a relatively
long history. “It is difficult to
justify widespread antibiotic prescribing for uncomplicated lower respiratory
infection on this basis, given the dangers of antibiotic resistance.”
I
was somewhat surprised at the duration of cough symptoms in this group of
patients—a mean total of 3 weeks. However, I believe most patients would
experience a gradual improvement over this period. We are admonished to
consider pertussis in patient with LRI when the cough lasts 3 weeks or more. I
presume in pertussis the cough continues unabated.
I
believe advising patients that antibiotics may be associated with serious
adverse effects (eg, colitis) will do more to tilt them toward accepting only
symptomatic therapy than would advising them of the danger of antibiotic
resistance in the community.
I
have had success in prescribing delayed prescriptions of patients with
uncomplicated lower respiratory infections. The great majority never fills the
prescription. This may be an acceptable means of satisfying a demanding
patient.
In
the
The
decision by primary care clinicians to prescribe or not prescribe, I believe,
will often depend on how “sick” the patient appears.
Potentially A Less Intimidating
Alternative to Warfarin. Concerns about
Hepatotoxicity
2-7 XIMELAGATRAN—Promises and Concerns
Melagatran is a highly-specific direct thrombin inhibitor,
an analogue of hirudin, the thrombin inhibitor found in the medicinal leech. It is a small dipeptide which binds
reversibly to the active site of thrombin. It inhibits clot-bound thrombin as
well as free thrombin. Ximelagatran is a prodrug form of melagatran. It is
rapidly absorbed from the GI tract. When given orally it is rapidly converted
to melagatran. Its antithrombin activity is immediate. Peak blood levels are
attained in 3 hours. It is cleared entirely by renal excretion in 12 hours.
Since
the effect is predictable at a fixed dose, monitoring is not necessary.
This
is not yet a practical point for primary care since the drug is not yet
approved by the FDA. Many attributes of
the drug make it a very attractive anticoagulant: immediate action when given orally; a fixed dose
without need for monitoring; rapid renal clearance; no food or drug interactions; active against clot-bound as well as free
thrombin; reversible binding to
thrombin.
If
the risk of hepatotoxicity can be controlled by monitoring, I believe it will
be a major therapeutic advance.
Warfarin Provided No Benefit Over Aspirin. Was
Associated With More Adverse Effects.
3-7 COMPARISON OF WARFARIN AND ASPIRIN FOR
SYMPTOMATIC INTRACRANIAL STENOSIS.
Randomized, double-blind multicenter
(59 sites) trial entered over 550 patients (mean age 63). All
had experienced a TIA or a non-disabling
stroke caused by angiographically verified 50% to 99% stenosis of a major
intracranial artery (internal carotid, middle cerebral, vertebral, or basilar).
Randomized to: 1) warfarin—target INR of 2.0 to 3.0, or 2)
aspirin 650 mg twice daily.
Warfarin provided no benefit over
aspirin. It was associated with significantly higher rates of adverse events.
“Aspirin should be used in preference to warfarin for patients with
intracranial arterial stenosis.”
This is a good example of a pragmatic (real world of practice) trial.
Difficulty in control of warfarin dosage may have been the cause of its lack of
benefit.
“Our Most Important Finding Was The High Level Of
Antipsychotic Prescribing In NHs.”
6-6 THE
QUALITY OF ANTIPSYCHOTIC DRUG PRESCRIBING IN NURSING HOMES
Antipsychotic drug prescribing in
nursing homes (NHs) has been rising.
Federal statutes are in effect to
protect NH residents from receiving inappropriate antipsychotics. They may be
appropriately prescribed for delirium and dementia only if psychotic features
or dangerous behaviors are present. Guidelines also stipulate maximum daily
doses.
For residents with dementia,
behavioral assessments must also show evidence of verbal or physical aggression
or delusions or hallucinations.
Impaired memory, wandering,
restlessness, unsociability, uncooperativeness, and indifference to
surroundings are NOT indications.
Use of antipsychotic drugs in NHs was
widespread. Most atypicals were prescribed outside the prescribing guidelines
with doses, and for indications without strong clinical evidence of benefit.
About 1 in 4 received doses exceeding recommended. About 2/3 of use was
appropriate—dementia with aggressive behavior; dementia with delusions;
psychotic disorder. About 1/3 received the drugs inappropriately—impaired
memory; depression without psychotic
features; indifference to surroundings;
insomnia; anxiety; wandering; restlessness; uncooperativeness; unsociability.
The study failed to detect positive
relationships between behavioral symptoms and antipsychotic therapy.
“This study raises questions about
the current uses of antipsychotics in NHs.”
These are powerful drugs. Elderly patients are subject to more adverse
effects. They require a lower dose because of impaired renal function and
concomitant illness. The PDR reiterates that schizophrenia is the only
indication. There is no mention of use in nursing homes. Few studies have
concerned patients over age 65.
I believe the most appropriate question to ask when contemplating use of
antipsychotics in NHs is...
Am I prescribing this drug to benefit
the patient, or the nursing staff and the family? This can be a most difficult
decision to make. If they are prescribed, individual-
patient’s response must be carefully monitored.
The NNT to Prevent One Stroke is Very High
Use of aspirin in primary prevention in women is
controversial. The current recommendations for use of aspirin in primary prevention in women are based on
limited data.
The Women’s Health Study was a large,
randomized, double-blind placebo-controlled trial of low-dose aspirin in the
primary prevention of cardiovascular disease among over 39 000 apparently
healthy women followed for a mean of 10 years for major cardiovascular events.
For the entire group of women over
age 45, aspirin reduced risk of ischemic stroke. It did not protect against
myocardial infarction and death from cardiovascular causes until after age 65.
Women taking aspirin experienced
significantly more GI hemorrhages (RR = 1.40)
By my calculation, between 500 and 900 individuals would need to be
treated for 10 years to prevent one ischemic stroke. Is this clinically
significant?—especially when the increased risk of hemorrhage is
considered. RTJ)
Thus far, studies indicate that, in men, the prophylactic benefit against
first occurrence of myocardial infarction is much greater than in women. But in
men, aspirin does not provide primary protection against stroke.
“No Indication Of A Net Benefit.”
Current
“Prophylactic use of a potentially
toxic agent can be problematic, particularly in people in whom comorbidity and
polypharmacy are common.” In a prospective observational study in two large
This epidemiological modeling study
was conducted in a hypothetical population (10 000 men and 10 000 women)
selected from a reference population from a state in
Proportional benefit gained from aspirin
in prevention of MI and ischemic stroke vs
excess hemorrhage from age 70-74 to age 100 or to death:
Benefit in preventing Men (n = 10
000) Women (n = 10 000)
Myocardial infarction - 389 - 321
Ischemic stroke - 19 - 35
Harm
Excess GI hemorrhage +
499 + 572
Excess hemorrhagic stroke + 76 + 54
When comparing net harms vs net benefits of aspirin, the effects
on length and quality of life were equivocal.
“Despite sound evidence for efficacy,
the temptation to blindly implement low-dose aspirin treatment for the primary prevention of cardiovascular
disease in elderly people must be resisted.”
Benefits may be offset by harms.
I believe low-dose aspirin has an important place in primary prevention
of women at higher risk, and in secondary prevention of cardiovascular disease.
There is an important clinical downside related to universal prophylactic
aspirin therapy: suppose primary care clinicians
prescribe low-dose aspirin to 1000 women over 10 years. Three or 4 ischemic
strokes might be prevented. But there would be no way of knowing which
individuals of the 1000 benefited. Conversely, a serious hemorrhagic event
occurring in 2 of the1000 patients would be self-evident. The clinician might
feel responsible, and the patient and family might blame the clinician for the
disaster.
I believe primary prevention with aspirin in women at average risk should
be avoided. Obviously, careful clinical judgment based on individual-patient
attributes is required.
Rate Control of AF Appears to be at
Least Equivalent to Rhythm Control.
2-4 RATE VS RHYTHM CONTROL IN PATIENTS WITH
ATRIAL FIBRILLATION
Patients with AF have a 4- to 5-fold
increase in risk of stroke and a 2-fold increase in risk of death. Because of
the frequency of AF at present, and its increasing incidence as the population
ages, there are enormous implications regarding AF-associated stroke, and its
prevention.
The two fundamental approaches to
management are 1) reestablishment and maintenance of sinus rhythm (rhythm
control), and 2) control of ventricular rate by intraventricular node blocking
agents (rate control).
“The results of our meta-analysis
suggest that in most patient populations with persistent AF, or at high risk of
recurrent AF, a strategy of maintaining rhythm control does not translate into
significant benefit on survival compared with a strategy of rate control in
combination with anticoagulation...”
Indeed, the suggestion is that rhythm
control may actually be inferior in regard to survival.
Compared to patients in normal sinus rhythm (NSR) ,
patients with AF have more heart-related symptoms and less efficient
ventricular function, decreased exercise tolerance, higher risk of stroke,
lesser quality of life, a requirement for anticoagulation, and shorter
survival. If restoration and maintenance of NSR, could
be accomplished easily and safely and could be constantly maintained, outcomes
would be more favorable than among patients with persistent AF. The problem is
that NSR may be difficult to achieve and maintain, and the drug therapy
required is toxic and often has to be withdrawn.
Many patients for whom rhythm control is attempted revert to AF and are
later crossed over to rate control. If anticoagulation is adequate in the AF patients,
risk of stroke is low.
Practical Pointers has previously abstracted two studies which arrived at
the same conclusion—rate control is not inferior to rhythm control. I thought
the point deserved emphasis. See www.practicalpointers.org December 2002 [12-2]
Aromatase Inhibitor Safer and More Effective
Than Tamoxifen
This study compared the
aromatase inhibitor anastrozole with tamoxifen over 5 years.
Compared with tamoxifen,
anastrozole led to significant improvements for disease-free survival, and
time-to-recurrence, especially in women whose BC was hormone-receptor-positive.
Benefits were also demonstrated in
hormone-receptor-negative patients.
Benefits were therefore in addition to the risk reduction
previously shown in tamoxifen vs placebo trials. (Ie, anastrozole vs placebo would have shown greater absolute benefits
compared with tamoxifen vs placebo)
The incidence of
contralateral BC was substantially reduced by anastrozole as compared with
tamoxifen. (This was also an improvement over the benefit of tamoxifen alone vs
placebo as demonstrated in previous studies.)
Withdrawals were
significantly fewer in the anastrozole group (11% vs 14%).
Drug-related serious
adverse events were also fewer (5% vs 9%).
Anastrozole was associated with significant
reductions in endometrial cancer, thromboembolic events, ischemic
cerebrovascular events, vaginal bleeding, and hot flushes.
Arthralgias and fractures were more frequent in
the anastrozole group. (The authors
suggest concomitant bisphosphonate therapy because of this finding.)
It is reasonable to
switch patients currently on tamoxifen to an aromatase inhibitor. It is not
appropriate to wait until after a 5-year period of treatment with tamoxifen.
The most effective and well-tolerated therapy should be offered at the earliest
opportunity.
Anastrozole should be considered the preferred initial adjuvant endocrine therapy for
post-menopausal women with hormone-receptor positive localized BC.
Aromatase is the enzyme which catalyses conversion of androgens to estrogens in
females. Aromatase inhibitors block production of estrogen..
There are three 3rd generation compounds under investigation: exemestane,
anastrozole, and letrozole. The action of exemestane is irreversible.
A similar study reported in NEJM March 11, 2004 reported
similar benefits when exemestane was substituted for tamoxifen after 2 to 3
years.(See Practical Pointers March 2004 [3-9] )
I believe this represents a major improvement in therapy of
BC, and likely an improvement in prevention.
I wonder—would there be any benefit in treatment of ductal
carcinoma in situ?
Usually Self-Limited and Typically Heal Without Medical
Intervention
2-6 BITES
OF BROWN RECLUSE SPIDERS AND SUSPECTED NECROTIC ARACHNIDISM
“Among both
physicians and the general public the perceived threat of spider bites far
exceeds the actual risk.” Loxosceles spider bites are the only proven medically
important cause of necrotic arachnidism in
Bites occur much
less commonly than as perceived by physicians and patients. The misdiagnosis of
spider bites is given to a wide spectrum of dermatologic conditions, some of
which are far more dangerous than a spider bite. (See the long list p. 703)
“Since many
diseases mimic loxoscelism, and since documented bites are rare, any diagnosis
of loxoscelism should be considered highly suspect.”
Treatment
remains controversial. Initial care should include routine first aid: elevation
and immobilization; application of ice; local wound care; and tetanus prophylaxis. A wide range of
other interventions has been reported, none with consensus regarding efficacy.
Many are costly, painful, and potentially toxic.
“Because the injury from the bite of
a brown recluse spider is usually self-limited and typically heals without
medical intervention, controlled trials would be essential to justify treatment
before advocating any particular therapy.” There is no therapy with proven
efficacy.
Even severe
necrosis is rarely life-threatening. The bite is typically self-limiting and
self-healing.
Patients often
overemphasize spider involvement in idiopathic wounds, a tendency that can
misdirect physicians toward an erroneous diagnosis. “Physicians should be
skeptical of any undocumented history of spider bite and should entertain a
broad differential diagnosis before attributing a skin ulcer as loxoscelism.”
Conservative use of simple first aid
and local wound care may be the best approach.
This sensible report may save some patients considerable discomfort.
Fasting Serum Glucose Level and Diabetes were Associated with
Cancer Risk
1-15 FASTING SERUM GLUCOSE LEVEL AND CANCER RISK
IN KOREAN MEN AND WOMEN
Is
there any connection between diabetes and cancer? Some observational studies
have suggested there is. This prospective cohort study investigated this
possibility.
A
ten-year prospective study enrolled over 829 000 men and over 468 000 women age
30 to 95 at baseline. (Mean = 46; mean body mass index = 23)
After
adjusting for smoking and alcohol use, the stratum with the highest fasting
glucose (> 140) had higher death rates from all cancers compared with the
stratum with the lowest level (< 90).
Hazard ratio = 1.25
Age-adjusted
cancer deaths per 100 000 men rose linearly from about 600 in the groups with
fasting glucose < 90 to about 1400 per 100 000 in the group with glucose
levels above 140. (Although absolute
numbers are low, the linear relationship depicted on page 196 and 200 is
impressive. RTJ).
Similar linear increases were recorded in women, although not as high in
absolute terms. Incidence of cancer was similar to mortality.
The association
was strongest for pancreatic cancer. (Hazard ratio = 2 comparing the highest
glucose stratum with the lowest.)
Significant associations were also found in other cancers (esophagus,
colo-rectal, liver, cervix).
”We
have shown that fasting serum glucose level and diabetes are associated with
cancer risk in a population far leaner than the Western populations.”
This is my first encounter with the
relation between glucose intolerance and cancer. It is not a clinically
important point now. I felt it was
interesting enough to abstract. I will watch for follow-up studies.
Absolute risk of a cardiovascular
disease is the probability that an individual
patient will have an event over a defined period. It is determined by a
synergistic effect of all CVD risk
factors present in the individual. It may be true that, in a large group of
individuals with a systolic BP of 160, the CVD risk is twice as high as in a large group with a
systolic of 110 (relative risk). In
an individual, however, absolute risk depends on much more than a single risk
factor. Indeed, absolute differences in risk can vary more than 20-fold in
patients with the same BP.
“Cardiovascular
treatment benefit is directly proportional to the pre-treatment absolute risk.”
A
new approach to preventive therapy is to modestly reduce all modifiable risk
factors rather than concentrating on reaching “target levels’ of one or two.
This is a sea change in our approach to
lowering risk.
Please read the full
abstract.
The NNT to Prevent One Stroke is Very High
Use of aspirin in primary prevention in women is
controversial. The current recommendations for use of aspirin in primary prevention in women are based on
limited data.
The Women’s Health Study was a large,
randomized, double-blind placebo-controlled trial of low-dose aspirin in the
primary prevention of cardiovascular disease among over 39 000 apparently
healthy women followed for a mean of 10 years for major cardiovascular events.
For the entire
group of women over age 45, aspirin reduced risk of ischemic stroke. It did not
protect against myocardial infarction and death from cardiovascular causes
until after age 65.
Women taking aspirin experienced significantly
more GI hemorrhages (RR = 1.40)
By my
calculation, between 500 and 900 individuals would need to be treated for 10 years to prevent one ischemic stroke. Is this clinically
significant?—especially when the increased risk of hemorrhage is considered. RTJ)
Thus far, studies indicate that, in men, the
prophylactic benefit against first occurrence of myocardial infarction is much
greater than in women. But in men, aspirin does not provide primary protection
against stroke.
Treat the Patient, Not the Blood
Pressure—Not the Cholesterol.
Absolute risk of a cardiovascular
disease is the probability that an individual
patient will have an event over a defined period. It is determined by a
synergistic effect of all CVD risk
factors present in the individual. It may be true that, in a large group of
individuals with a systolic BP of 160, the CVD risk is twice as high as in a large group with a
systolic of 110 (relative risk). In
an individual, however, absolute risk depends on much more than a single risk
factor. Indeed, absolute differences in risk can vary more than 20-fold in
patients with the same BP.
“Cardiovascular
treatment benefit is directly proportional to the pre-treatment absolute risk.”
A
new approach to preventive therapy is to modestly reduce all modifiable risk
factors rather than concentrating on reaching “target levels’ of one or two.
This is a sea change in our approach to
lowering risk.
Please read the full abstract.
Injecting New Enthusiasm into the Dietary Management of
Hyperlipidemia
5-1 THE EFFECT OF A
PLANT-BASED DIET ON PLASMA LIPIDS IN HYPERCHOLESTEROLEMIC ADULTS
Dietary modifications to lower
LDL-cholesterol have focused on avoiding saturated fats and cholesterol. They
often result in only modest improvement.
This traditional
focus of lipid management may have been overly simplistic. Diets may be more
effective if more attention were focused on including
certain foods rather than just avoiding
saturated fat and cholesterol. Several
foods such as soy protein, plant sterols, soluble fiber, oats, nuts, and garlic
have potential lipid benefits. Each is derived from plants. They contain little
saturated fat and no cholesterol.
This study theorized that the
lipid-lowering benefits of a plant-based diet would be greater than a more
conventional low fat-diet under conditions in which both diets contained the
same amount of total fat, saturated fat, and cholesterol, and the weight was
held steady.
Subjects were randomized to:
1) Low Fat diet. Consistent with former American Heart
Association step 1 guidelines:
2) Low-Fat Plus diet. Consistent with
the AHA year 2000 guidelines:
Kept saturated fat under 10% but
added increased intakes of vegetables and whole grains—in general a plant-based
diet. It contained considerably more vegetables, legumes, whole grains, and
fruits. Soy protein (~ 16 g per/2000 kcal) and fresh garlic (~ 1.5 cloves) were
used daily.
Butter, cheese, and eggs were added
to the low-fat plus diet to increase the saturated fat and cholesterol content
to match the low-fat diet. Both diets provided 30% of energy from total fat; 10% from saturated
fat; and about 100 mg cholesterol per 1000 kcal.
Change at 4 weeks (means): Low-fat
Plus Low-fat
Total cholesterol (mg/dL) -18 -9
LDL-cholesterol (mg/dL) -14 -7
In moderately hypercholesterolemic
individuals a plant-based low-fat diet achieved a significantly greater reduction in
LDL-c than the standard low saturated fat diet.
The differences are not attributable
to saturated fat, cholesterol, energy intake, or body weight because each of
these variables was kept constant in the 2 groups.
This puts a new slant on treatment of dyslipidemia. Patients may be told
that including 1, 2 or 3 selected foods daily will actually treat their cholesterol.
When To Intervene? How To Intervene?
6-7
THRESHOLDS FOR NORMAL BLOOD PRESSURE AND SERUM
CHOLESTEROL.
In 2003,
European guidelines suggested a BP of above 140/90, and a
cholesterol above 5 mmol/L (193 mg/dL) as the appropriate thresholds for
intervention. “The bottom line is that the doctor is expected to inform the
patient that these measurements mean that he or she is at increased cardiovascular
risk regardless of the management proposed.
In other words, a disease label is to be attached to the patient.”
In
The potential
benefits for treated patients become less at lower risk levels. The number
needed to treat is increased. The rates of adverse effects (of drug treatment)
remain the same. Adverse effects tend to be under-reported and under-published.
Certainly, experts who developed these
guidelines did not suggest that all persons with BP and cholesterol levels
above these cut-points should be treated with drugs.
I
believe however, that all should be treated with judicious advice about
changing in lifestyle. This will apply to almost all persons in the
I
do not believe life-style advice will be interpreted as a labeling of disease.
There are few if any adverse effects of lifestyle changes. Effectiveness is
established. The benefit/harm-cost ratio is very low.
The
task of educating patients about healthy lifestyles and getting them to adopt
them is daunting, and in the main unsuccessful. We should not be deterred from
trying. This includes primary care clinicians’ adopting a healthy lifestyle
themselves.
Who
should be treated with drugs?—patients who are indeed at high risk. The
definition of “high risk” depends not only on the number or risk factors
present and their levels, but also on the individual patient’s assessment of
his own risk. Patients must be convinced of the benefits of drug therapy; must understand
that drug therapy is long-term, expensive, and carries risks of its own.
One or Two Drinks per Day may Reduce
Risk of Cognitive Decline
1-12 EFFECTS OF MODERATE
ALCOHOL CONSUMPTION ON COGNITIVE FUNCTION IN WOMEN.
This
study asks—What is the effect of moderate consumption of alcohol on cognition? A benefit is
plausible considering the strong link between moderate alcohol and decreased
risk of cardiovascular disease. Cognitive impairment and cardiovascular disease
share common risk factors.
Compared
with abstainers, moderate drinkers (less than 15 g alcohol per day; one drink)
had better mean cognitive scores. (Relative risk of impairment = 0.81 based on
a global cognitive score.) Also,
compared with abstainers, moderate drinkers (15 to 30 g per day) had a reduced
relative risk of cognitive impairment (although slightly less favorable, with
wider confidence intervals).
In
older women consumption of one alcoholic drink per day did not impair cognitive
function, and may actually decrease risk of cognitive decline.
Benefits of moderate alcohol consumption
have been reported with remarkable consistency over the past 10 years. Indeed,
some epidemiologists consider abstinence to be a risk factor for cardiovascular
disease.
As always, we should be cautious about generalizing the conclusions of
observational studies.
Donepezil May Delay Clinical Progression To
Alzheimer’s Disease
6-10 VITAMIN E AND DONEPEZIL (ARICEPT) FOR THE TREATMENT OF MILD
COGNITIVE IMPAIRMENT
Amnestic (memory loss)
mild cognitive impairment (MCI)
represents a transitional state between the cognitive changes of normal aging
and the earliest clinical features of Alzheimer’s disease (AD). Amnestic MCI refers to the
subtype that has a primary memory component, either alone or in conjunction
with other cognitive-domain impairments, of insufficient severity to constitute
dementia. About 80% of those who meet the criteria for MCI will have AD within
6 years.
MCI is a
transition state between normal aging and dementia (for Alzheimer’s disease in
particular), one in which cognitive deficits are present, but function
preserved. In clinical settings, the term is often used to describe patients
who present with memory loss, but do not have dementia. Even when defined
carefully, MCI is a heterogeneous category that includes some persons with
memory changes of normal aging, some with non-progressive cognitive defects,
some with prodromal AD, and some with prodromal forms of other
neurodegenerative dementias.
This study was
designed to determine if vitamin E or the cholinesterase inhibitor donepezil
could delay the clinical diagnosis of AD in patients with MCI.
Vitamin E had no
effect at any time.
For donepezil .
. . “The observed relative reduction in the risk of progression of 56% at one
year and 36% at two years in the entire cohort is likely to be clinically
significant.”
“Although our
findings do not provide support for a clear recommendation for the use of
donepezil in persons with mild cognitive impairment, they could prompt a
discussion between the clinician and the patient about this possibility.”
Symptoms of
memory loss in older persons should be taken seriously. They may represent the
beginning of AD. This may be an important clinical measure
once more effective treatments become available.
The important
question is . . . What are the cognitive changes of normal aging?
I
believe some degree of memory impairment is almost universal among individuals
over age 80. It usually
begins by forgetting names, and recalling
them minutes or hours later ( “senior moments”). The spectrum of memory
impairment is wide. The definition of amnestic MCI is not settled. At what
point does it predict development of AD? The criteria for diagnosis of amnestic
MCI in the study included patients with difficulties greater than temporarily
forgetting names.
This
study may foretell important developments in drug therapy which may delay the
onset of disabling dementia. The spectrum of forgetfulness of old age is very
broad. When should intervention be considered?
Some elderly patients may well accept
early intervention. A delay of one to two years represents a large proportion
of remaining quality-life. Patients may be willing to accept some adverse
effects of drugs to gain a few years free of dementia of AD. (Note that
anticholinergics do not benefit vascular dementia.)
Others
may wish to wait until adverse effects on daily living become more evident.
I
do not believe memory defects inevitably progress to AD. Keeping mentally and
physically active, continuing a healthy diet, retaining active family and
social connections, and controlling risk factors for cardiovascular disease
will delay or prevent development of dementia in many individuals.
CORONARY HEART DISEASE (See also ISCHEMIC
HEART DISEASE [5-2])
All Adults in the
3-1 RELATIVE IMPORTANCE OF BORDERLINE AND
ELEVATED LEVELS OF CORONARY HEART DISEASE RISK FACTORS
Prospective cohort study (The
Framingham Study) and a national cross sectional survey (Third National Health and Nutrition Examination Survey) considered a
large group of white, non-Hispanic persons between ages 35 and 74. (Mean age =
50)
Determined the first CHD event
(defined narrowly as a myocardial infarction or cardiac death over 10-years ) related to five major CHD risk factors: BP, LDL-cholesterol, HDL-cholesterol, glucose
intolerance, and smoking.
Assigned three
categories to each risk factor—elevated, borderline, and optimal.
Optimal Borderline Elevated
Systolic BP under120 120-139 over 139
Diastolic BP under 80 80-89 over 89
LDL-cholesterol under100 100-159 over159
HDL-cholesterol over 59 59-40 under
40
Other borderline factors:
Impaired fasting glucose (110-123)
Past history of smoking
Other elevated risk factors
Diabetes
Smoking
Optimal levels of all 5 risk factors
were rarely present in any age group or in either sex.
Seventy four % of men and 59% of
women had one or more elevated risk factors. Twenty six % of men and 41% of
women had at least one borderline risk factor. (Note: this adds up to 100%)
The authors estimate that, for ages
35-74, over a 10-year period, nearly 4.7 million white men and over 1 million
white women in the
I believe this study presents too narrow a view of the cardiovascular
disease problem in the
1) Ten years is too short a time to assess the overall risk
of disease. The atherosclerotic process begins decades earlier and ends decades
later.
2) Only 5 risk factors were considered. There are many others
for which we should intervene: body mass index, dietary factors, physical
fitness, intra-abdominal fat, triglycerides, C-reactive protein, abstinence
from alcohol. The object of prevention should be to lower every individual risk
factor as much as possible considering safety and cost. The number of risk
factors far exceeds those chosen by the study.
3) The definition of disease was too narrow. (Only
cardiac death and myocardial infarction.)
This eliminates consideration of other acute coronary syndromes, stroke,
vascular dementia, peripheral vascular disease, and aortic aneurysm.
4) The study arbitrarily divided the cohort into 3 subgroups
of risk—elevated, borderline and optimal and assumed the risk was equal in
every individual in each cohort. The study did not consider the considerable
differences in risk of disease associated with varying levels of the risk factors in each of the 3 groups. Risk rises
and falls linearly. An individual with a LDL-cholesterol of 110 (borderline)
has lower risk than one with a LDL-c of 145 (still borderline). A person with a
systolic BP of 145 (elevated)
is at much lower risk than one with a systolic of 175 (also elevated).
This article tilts toward
the traditional practice of screening to identify higher risk associated with a relatively few
risk factors, and vigorously treating
each individual risk factor. Is screening, and treating, and retesting every one of 5 “elevated” risk factors
the best approach? This is certainly not practical when applied to the entire
at-risk population. (Essentially the whole population in the
All risk factors add to risk
in all individuals in our high-risk culture. They should be treated empirically
.and lowered concomitantly. Laboratory testing may be minimized.
Atherosclerosis is an essentially preventable disease. We have failed miserably in our efforts to
prevent it.
We need to apply a new population-based approach to prevention.
The approach changes for patients with established atherosclerotic
disease. Risk reduction should be applied vigorously to all factors. RTJ
Drug And Lifestyle Modifications Are Beneficial Regardless Of
The Initial Level Of The Risk Factor.
3-2 THE
MIDDLE-AGED AND OLDER AMERICANS; WRONG PROTOTYPE FOR A PREVENTIVE
POLYPILL?
(This editorial comments and expands on the preceding article.)
Most Americans older than age 55 have
one or more risk factors for cardiovascular disease” 1/3 or more have
hypercholesterolemia, 1/5 smoke, most have inactive lifestyles, 1/3 have high BP. About 1/3 are obese, about 1/10 have
diabetes.
Americans have a dizzying array of
options to reduce risk. Preventive approaches aimed primarily at identifying
and treating individual risk factors were popular in the 1980s and 1990s but
had limited success.
Experts now recommend assessment of
an individual’s global risk for
vascular disease when deciding whether to treat risk factors, and when
selecting specific target levels for those risk factors.
In 2003 Wald and Law1 proposed a radical population-based
strategy that they claimed would reduce cardiovascular disease by 80%, and have
greater impact on public health than any other preventive strategy. They
advised discarding the view that risk factors need to be measured (and treated
individually if found to be ‘abnormal’).
Instead they advocated treating all
adults older than age 55 with a “Polypill” containing low doses of a
statin, folic acid, aspirin, and 3 antihypertension drugs. (Low-dose presumably
would be associated with fewer adverse effects.) This was based on the premise that risk
factors are present in everyone in
Western societies, and determination of individuals’ global risk is not
necessary, and that 96% of deaths from vascular disease occur in people over
age 55. Monitoring each individual’s risk factor level to assess treatment
benefits is of limited usefulness.
Risk factor interventions with drugs
and lifestyle modifications are effective whatever the initial level of the
risk factor.
The editorialists comment that treating everyone older than age 55
with a low-dose Polypill without measuring risk factors may be too audacious
for Americans. Adverse effects will likely occur from these multi-drug pills in
low risk patients who have little potential for benefit.
When I first read of the Polypill, I thought the authors were suggesting
the concept “tongue in cheek”. Subsequently the concept gained considerable
attention and comment.
The premise of the Polypill:
1) All persons have
risk factors for CVD. There is no cut point below which risk is not evident,
and no cut point above which risk does not increase.
2) The Polypill reduces 4 risk
factors (BP, LDL-c, platelet aggregation, and homocysteine). The benefit from
lowering all 4 is additive, although not equally.
The Polypill is limited to drug therapy. And only in persons over age 55. The range of risk factors is much larger, and
the atherosclerotic process begins at a much younger age. Many individuals experience a CVD event at an
early age.
Each risk factor (lifestyle and clinical) adds to risk. When each risk factor is reduced, (even if
only modestly) benefit increases additively.
Primary care clinicians and their patients tend to focus on measuring and
treating only a few risk factors (eg, BP and cholesterol). Indeed “know your cholesterol” has become a
national imperative. In the mind of the
public achieving a “low” cholesterol is the best one
can do to prevent CVD. But, individuals
may have a LDL-c considerably below 100 and still be at high risk due to
presence of other factors.
.What to do? 1) Treat everyone
empirically, or 2)
Treat only select individuals after screening. If you concede
that everyone is at risk, you must choose 1). Treating everyone with drug
therapy is too drastic a measure. Lifestyle measures begin at an early age and
modifying them can reduce risk without adverse effects. More clinicians may now
be encouraged to list
all risk factors in their individual patients and point out the additive effect
of lowering each of them.
I believe atherosclerosis is essentially a preventable disease. Our
attempts at control are failing miserably. Americans refuse to adopt preventive
lifestyles. Primary care clinicians have failed to adequately educate the
public.
Once atherosclerotic disease becomes established, treatment changes to
all-out reduction of risk factors. RTJ
“No Indication Of A Net Benefit.”
Current
“Prophylactic use of a potentially
toxic agent can be problematic, particularly in people in whom comorbidity and
polypharmacy are common.” In a prospective observational study in two large
This epidemiological modeling study
was conducted in a hypothetical population (10 000 men and 10 000 women)
selected from a reference population from a state in
Proportional benefit gained from
aspirin in prevention of MI and ischemic stroke vs excess hemorrhage from age 70-74 to age 100 or to death:
Benefit in preventing Men (n = 10
000) Women (n = 10 000)
Myocardial infarction - 389 - 321
Ischemic stroke - 19 - 35
Harm
Excess GI hemorrhage + 499 + 572
Excess hemorrhagic stroke + 76 + 54
When comparing net harms vs net benefits of aspirin, the effects
on length and quality of life were equivocal.
“Despite sound evidence for efficacy,
the temptation to blindly implement low-dose aspirin treatment for the primary prevention of cardiovascular
disease in elderly people must be resisted.”
Benefits may be offset by harms.
I believe low-dose aspirin has an important place in primary prevention
of women at higher risk, and in secondary prevention of cardiovascular
disease.
There is an important clinical downside related to universal prophylactic
aspirin therapy: suppose primary care
clinicians prescribe low-dose aspirin to 1000 women over 10 years. Three or 4
ischemic strokes might be prevented. But there would be no way of knowing which
individuals of the 1000 benefited. Conversely, a serious hemorrhagic event
occurring in 2 of the1000 patients would be self-evident. The clinician might
feel responsible, and the patient and family might blame the clinician for the
disaster.
I believe primary prevention with aspirin in women at average risk should
be avoided. Obviously, careful clinical judgment based on individual-patient
attributes is required.
A mnemonic for diabetes. The editor tried to create a check
list for diabetes:
D Diet; Depression
I Insulin
A Aspirin; ACE
inhibitors
B BMI; BP
E Exercise
T Tests (blood glucose; HbA1c; lipids;
microalbuminuria; liver function; ejection fraction)
E Eye (retinopathy); Extremities (foot
health; foot pulses; peripheral neuropathy)
S Sulfonylureas, Statins, and other oral
drugs; Smoking
Fasting Serum Glucose Level and Diabetes were Associated with
Cancer Risk
1-15 FASTING SERUM GLUCOSE LEVEL AND CANCER RISK
IN KOREAN MEN AND WOMEN
Is
there any connection between diabetes and cancer? Some observational studies
have suggested there is. This prospective cohort study investigated this
possibility.
A
ten-year prospective study enrolled over 829 000 men and over 468 000 women age
30 to 95 at baseline. (Mean =
46; mean body mass index = 23)
After
adjusting for smoking and alcohol use, the stratum with the highest fasting
glucose (> 140) had higher death rates from all cancers compared with the
stratum with the lowest level (< 90).
Hazard ratio = 1.25
Age-adjusted
cancer deaths per 100 000 men rose linearly from about 600 in the groups with
fasting glucose < 90 to about 1400 per 100 000 in the group with glucose
levels above 140. (Although absolute
numbers are low, the linear relationship depicted on page 196 and 200 is
impressive. RTJ).
Similar linear increases were recorded in women, although not as high in
absolute terms. Incidence of cancer was similar to mortality.
The association
was strongest for pancreatic cancer. (Hazard ratio = 2 comparing the highest
glucose stratum with the lowest.)
Significant associations were also found in other cancers (esophagus,
colo-rectal, liver, cervix).
”We
have shown that fasting serum glucose level and diabetes are associated with
cancer risk in a population far leaner than the Western populations.”
This is my first encounter with the
relation between glucose intolerance and cancer. It is not a clinically
important point now. I felt it was
interesting enough to abstract. I will watch for follow-up studies.
Treatment Reduced Serious Perinatal Morbidity In Infants And May Improve The Woman’s Health-Related
Quality Of Life.
6-12 GESTATIONAL DIABETES MELLITUS; Effect Of Treatment
On Pregnancy Outcomes.
Gestational
diabetes mellitus (GDM) occurs in up
to 9% of all pregnancies. It is associated with substantial maternal and
perinatal complications. Neonatal complications include macrosomia, shoulder
dystocia, birth injuries, bone fractures, nerve palsies, and hypoglycemia.
Long-term adverse health outcomes among infants born to mothers with GDM
include sustained glucose intolerance, subsequent obesity, and impaired
intellectual achievement.
This study asked
. . . Does screening and treatment for GDM reduce these risks?
This randomized
trial enrolled 1000 women who were between 16 and 30 weeks pregnant. Randomized
to: 1) An intervention group received
expert diabetes care including education, self-monitoring blood glucose, and
adjusted insulin therapy, and 2) A usual care group.
Serious perinatal complications in
infants were significantly lower in the intervention group (1% vs 4%). The NNT
to prevent one serious outcome in infants = 34.
Birth weights were lower in the intervention group (less likely to have
macrosomia). No difference in rate of
hypoglycemia requiring intravenous glucose.
Women in the intervention group
gained less weight and had less risk for preeclampsia. At 3-months postpartum,
women had lower rates of depression and higher scores on quality-of-life. Rates
of caesarean deliveries were similar.
Impaired glucose tolerance and diabetes are important risk factors at the
time of conception. Primary care clinicians can serve their young adult female
patients by advising them of the risks of glucose intolerance (and excessive
weight) before and at the time of conception.
Development May be Delayed by Good Glycemic Control and Modification of
Cardiovascular Risk Factors.
1-14 VASCULAR RISK
FACTORS AND DIABETIC NEUROPATHY
The
Diabetes Control and Complications Trial reported a 60% reduction in DN in the
intensively treated group at 5 years. But the incidence still remained substantial.
This suggests that DN can develop despite intensive control of glucose levels.
Risk factors other than glucose are involved.
This
study assessed potentially modifiable risk factors for development of distal,
symmetric DN.
Dyslipidemia, elevated BMI, smoking, and hypertension were
associated with development of DN.
Cardiovascular
disease at baseline was associated with double the risk of neuropathy.
What
can be done prospectively to try to prevent DN?
Control
glycemia as best it can be controlled
Stop
smoking
Control
BP
Control
weight, obtain lower body mass index
Reduce
other cardiovascular risk factors.
(Ie, essentially standard
diabetes management.)
I enjoyed reviewing the
diagnosis of neuropathy.
The mean age at baseline was about 30. Of an
initial cohort, 28%
already had DN.
Prospectively, over 7
years 23% developed DN. Thus at age about
40, over half had DN. I would expect
almost all patients with type 1 diabetes will eventually develop DN.
Adherence was Poor.
Those Who Adhered for One Year Lost Weight
This
study assessed adherence rates and effectiveness of 4 diets in producing weight
loss and reducing cardiac risk factors:
1. Atkins Low carbohydrate—20 g
carbohydrate daily
2. Zone High protein, low
glycemic load
3. Weight Watchers Balanced diet—total daily
”points” in a range determined by current weight (Aimed for 24 to 32 points daily.)
4. Ornish Low fat, vegetarian
diet containing 10% of calories as fat.
About half of
the subjects in each group failed to complete the 1-year course. The most
common reasons were “too hard to follow” and “not yielding enough weight loss”.
Adherence was particularly low for Atkins and Ornish.
At 1 year,
completers lost more than those who failed to complete ( - 3. 9 kg for Atkins and -6.6 kg for
Ornish)
Each diet
significantly reduced LDL/HDL-cholesterol ratio by about 10%. The Atkins diet
did not lower LDL-cholesterol significantly. The Ornish diet did not increase
the HDL-cholesterol. No diet significantly altered triglyceride levels.
Reductions of total cholesterol, C-reactive protein, and insulin levels were
significantly associated with the degree of weight loss.
Under realistic
conditions a variety of popular diets can reduce weight and several cardiac
risk factors. But only about half of the subjects in this study sustained a
high adherence level.
The
problem is not the diet, it is the patient’s inability
to follow it. Recidivism would be higher still at 5 or 10 years. The bloom seems to be coming off the Atkins
diet.
The
authors suggest that one way to improve dietary adherence in clinical practice
may be to use a broad spectrum of diet options to better match individual
patient’s food preferences, lifestyles, and cardiovascular risk factors. They
suspect adherence would have been better if subjects had been given the option
to choose their diet.
I wonder—would switching
from one type of diet to another every few months increase compliance?
Associated with longer
survival.
4-4 MODIFIED MEDITERRANEAN DIET AND SURVIVAL
The
Mediterranean diet (MD) is
characterized by a high intake of vegetables, legumes, fruits, and cereals
(largely unrefined); a moderate to high intake of fish; a low intake of
saturated fats; a high intake of unsaturated fats (particularly olive oil); low
to moderate dairy products; a low intake of meat; and a modest intake of
ethanol, mostly as wine.
This
study examined whether adherence to a modified MD (poly-unsaturated fats
substituted for mono-unsaturates) was associated with longer life expectancy
among elderly Europeans.
Means
scores on the 10-point MD scale varied considerably between countries.
An
increase in this modified MD score was associated with lower overall mortality.
A two-unit increment corresponded to a reduction on 8% in mortality.
I believe the modification
(substituting poly-unsaturated fats for mono-unsaturated fat) is a clinically
important point. Poly-fats are more accessible in our culture than mono-fats.
Injecting New Enthusiasm into the Dietary Management of
Hyperlipidemia
5-1 THE EFFECT OF A PLANT-BASED DIET ON PLASMA
LIPIDS IN HYPERCHOLESTEROLEMIC ADULTS
Dietary modifications to lower
LDL-cholesterol have focused on avoiding saturated fats and cholesterol. They
often result in only modest improvement.
This traditional
focus of lipid management may have been overly simplistic. Diets may be more
effective if more attention were focused on including
certain foods rather than just avoiding
saturated fat and cholesterol. Several
foods such as soy protein, plant sterols, soluble fiber, oats, nuts, and garlic
have potential lipid benefits. Each is derived from plants. They contain little
saturated fat and no cholesterol.
This study theorized that the
lipid-lowering benefits of a plant-based diet would be greater than a more
conventional low fat-diet under conditions in which both diets contained the
same amount of total fat, saturated fat, and cholesterol, and the weight was
held steady.
Subjects were randomized to:
1) Low Fat diet. Consistent with former American Heart
Association step 1 guidelines:
2) Low-Fat Plus diet. Consistent with
the AHA year 2000 guidelines:
“The Moral Basis of the Right to Die is the Right to Good Quality
Life” “Mere Existence Is Not An Automatic Good.”
A general question is whether there such a thing as a right to die. The
editorialist believes there is for the following reasons:
1)
Every human rights convention recognizes a fundamental right to life.
2)
Paradoxically, as it might at first seem, this also entails a right to die.
A. Life in the phrase “the right to life” does not mean bare existence.
It means existence that has a certain minimum quality.
B.
Mere existence is not an automatic good
“It
is perhaps characteristic of humankind that it regards
reasoned choices about when and how to die as morally problematic, whereas ignoring
the question and hoping for the best is seen as acceptable or even right.”
Lawyers
and doctors distinguish between withholding treatment
with death as the result, and giving treatment that causes death. The first is
considered permissible in law and ethics. The second is not. “But in fact,
there is no difference between them.” Withholding treatment is an act, based on
a decision, just as giving treatment is an act based on a decision. “Like the doctrine of double
effect, which allows death-hastening levels of analgesia with the putative aim
of controlling pain, the distinctions are fictitious. Death, after all, is the
ultimate analgesic.”
This one page commentary sums it up nicely
Stool Antigen Test is Recommended
1-9 TEST AND TREAT FOR DYSPEPSIA: But Which Test?
The
National Institute for Clinical Excellence (NICE)
of the
Now
the stool antigen test is available. It detects H pylori antigens passed in feces. A commercial monoclonal antibody
test is available. It is reported to be as accurate as the urea breath test. It
can be introduced with ease into routine laboratory practice. It is less
expensive and less time consuming than the urea breath test. It is useful also in confirming eradication
of the infection.
“We
need to have an easy, accurate diagnostic test and the stool antigen test is
just that.”
There are some advantages of “test and treat”:
Will
treat an unsuspected peptic ulcer. And reduce risk of subsequent ulcer
disease.
Will reduce or
eliminate symptoms in some patients ( ~ 10%). Since about 50% of patients with functional dyspepsia will be
positive, eradication will remove symptoms in only 5% of patients with
dyspepsia.
Remove a risk factor
for gastric cancer.
Causes More Cancer Than It Prevents
5-7 ENDOMETRIAL
CANCER AND HORMONE REPLACEMENT THERAPY IN THE MILLION WOMEN STUDY
Estrogen-only hormone-replacement
therapy (HRT) increases the risk of
endometrial cancer (EC). To
counteract this effect, many postmenopausal women who have not had a
hysterectomy use combined HRT
(progestagen + estrogen). The
addition of progestagen attenuates or even reverses the estrogen-associated
increase in EC.
This large study
assessed the relation between different types of HRT and incidence of EC.
Relative risk of
EC compared with never-users:
Continuous combined HRT (progestagen
daily + estrogen daily—RR =
0.71 (A reduction in risk.)
Combined
cyclic HRT (progestagen 10 to 14 days/month—RR = 1.05 (No significant
alteration.)
Estrogen
alone—RR = 1.45 (Increased risk.)
But
the benefit in lowering risk of EC was greatly offset by a rise in breast
cancer.
Incidence rates
for endometrial cancer and breast cancer per 1000 women over 5 years:
Continuous combined Cyclic
combined Estrogen alone Never users
Endometrial
cancer 2.0 3.0 4.9 3.0
Breast
cancer 29 28 18 14
Thus, although continuous combined
HRT reduced risk of endometrial cancer by 1 in 1000 over 5 years, it was
associated with 15 more breast cancers. This is an increase in total cancers of
14 per 1000. Estrogen alone was associated with a lower risk (4 total cancers
per 1000 women over 5 years).
Combined
estrogen-progestagen causes a greater increase in breast cancer than a
reduction in EC. The net effect is an increase
in total cancer risk with use of HRT, especially combined HRT.
Progestagens, not estrogens, are the main factor increasing risk of BC.
Just think—another extraordinary sea change in clinical application. For
decades standard HRT practice insisted that, for women with a uterus, a progestagen
be added to estrogen. This on the pain of being accused of
malpractice.
Is the Evidence “Generalizable” to my
Patient?
1-3 EVIDENCE-BASED PRACTICE AND THE INDIVIDUAL
Is
my patient so different from those in the trial that its results cannot help me
make my treatment decision? The more family practitioners feel they know their
patients, the less likely they are to apply external evidence to guide management.
Disingenuous
surrogate markers and misleading composite outcomes may create good advertising
material, but cannot obscure data and hinder genuine patient-centered care.
Let
us not neglect the central role of individual patients as decision-makers in
their own care. “It is the responsibility of healthcare workers to communicate
objective evidence in a manner which allows recipients to make an informed
choice, and then to respect that choice.”
“Now
and then, clinicians will have to accept and explain that uncertainty is an
inherent facet of the uniqueness of human nature. Evidence helps to quantify
that uncertainty, but cannot remove it.
Why do we Underuse Treatments That are Beneficial in Trials?
1-2 EXTERNAL VALIDITY OF RANDOMIZED CONTROLLED
TRIALS: To Whom do the Results of this Trial Apply?
Randomized
controlled trials (RCTs) and
systematic reviews must be internally
validated. (Ie, the design and conduct of RCTs must keep the possibility of
bias to a minimum). To be clinically useful, however, the results must be
relevant to a definable group of patients in a particular clinical
setting. This is termed external validity.
The
most frequent criticism by clinicians of RCTs, systematic reviews, and
guidelines is the lack of external validity. This explains the widespread
underuse in routine practice of treatments that are beneficial in trials and
recommended by guidelines.
Assessment
of external validity requires clinical rather than statistical expertise.
The response to,
and compliance with, treatment can be influenced strongly by the doctor-patient
relationship, placebo effects, and patient preferences. The importance of these factors
outside of trials should not be underestimated. Note the popularity of
“alternative” therapies in which such factors are the
only active ingredients.
The primary care clinician
is a final arbiter of external validity. (Would this application be clinically
useful for Mrs. Jones? )
Beware of surrogate outcomes
in RCTs, of composite outcome measures, underreporting of adverse effects,
and reports by pharmaceutical companies.
Primary
care difficult, challenging, and so rewarding.
A Particularly Ominous Public Health
Issue
1-8 FAST-FOOD HABITS, WEIGHT GAIN, AND INSULIN
RESISTANCE
This study investigated the
association between fast-food habits of young
At
baseline, weekly visits to fast-food restaurants = 2.4 for men and 1.7 for
women. Younger subjects made more visits. There was a direct and independent
monotonic association between fast-food frequency and
weight and insulin resistance. Subjects who
visited three times a week had a mean weight about 2 kg higher than those who
visited less than once a week.
Over
15 years, frequent visitors gained more weight compared with those who visited
less than once a week.
Insulin resistance was directly
associated with visits of 3 times a week. There was a direct and independent
monotonic association between fast-food frequency and weight and insulin resistance. Compared with subjects whose
fast-food visits were less than once a week, those who visited over 2 times
weekly gained an extra 4.5 kg and
had a 104% greater increase in insulin resistance.
Fast-food
habits have strong, positive and independent association with weight gain and
insulin resistance in young adults. This suggests an increased risk of type 2
diabetes and obesity.
I am sure that this does not
surprise anyone.
The study points out some
differences between blacks and whites, and between males and females. See the
text.
“Overload your truck &
it will break down.”
The fast-food industry is
beginning to make some adjustments in their menus. This is difficult for a
highly competitive industry. To stay in business, the competition must be met.
Customers will frequent the establishments offering the best tasting foods and
the largest portion size. The solution lies, not in forcing the fast-food to
change their menus, but by making a sea-change in public awareness and
compliance with a “healthy diet”—an almost impossible task which will take years
to accomplish even partially.
GASTRO ESOPHAGEAL REFLUX DISEASE
The Test Could Be Used As An Initial Approach To Diagnosis.
Gastro
esophageal reflux disease (GERD) is
the most common cause of non-cardiac chest pain (NCCP). Patients with NCCP are often treated empirically and
successfully with proton pump inhibitors.
This study asked. . .Can proton pump inhibitors ( a PPI test) be used
as a diagnostic test?
Results of the
PPI test:
GERD present GERD absent
Positive test (> 50% relief) 80% (true positive)* 26% (false positive)
Negative test (< 50% relief) 20% (false negative) 74% (true negative test)**
(* sensitivity of the PPI test = true + % = 80%; **
specificity of the PPI test = true negative % = 74%)
Results of the placebo test:
Positive test (> 50% relief) 19% (true positive)*** 23% (false positive)
Negative test (< 50% relief) 81% (false negative) 77% (true negative test)****
(*** sensitivity of placebo test
=19%; **** specificity of placebo test = 77%)
Thus 80% responded favorably to PPI vs 19% to placebo.
Treatment with PPIs
and placebo showed similar effects (26% and 23%) on improving NCCP symptoms in
patients without GERD, indicating a
possible placebo effect.
The use of PPI as a diagnostic test
for detecting GERD in patients with NCCP has an “acceptable” sensitivity and
specificity and could be used as an initial approach by primary care physicians
to detect GERD in selected patients with NCCP.
“Acceptability of the test would be more meaningfully determined by
calculating pre-test probability., likelihood ratios,
and post-test probability. See the full
abstract.
Regardless of the modest diagnostic help given by a PPI test, I believe,
in practice, the test is used extensively by primary care clinicians and their
patients.
Treatment Reduced Serious Perinatal Morbidity In Infants And May Improve The Woman’s Health-Related
Quality Of Life.
6-12 GESTATIONAL DIABETES MELLITUS; Effect Of Treatment
On Pregnancy Outcomes.
Gestational
diabetes mellitus (GDM) occurs in up
to 9% of all pregnancies. It is associated with substantial maternal and
perinatal complications. Neonatal complications include macrosomia, shoulder
dystocia, birth injuries, bone fractures, nerve palsies, and hypoglycemia.
Long-term adverse health outcomes among infants born to mothers with GDM
include sustained glucose intolerance, subsequent obesity, and impaired
intellectual achievement.
This study asked
. . . Does screening and treatment for GDM reduce these risks?
This randomized
trial enrolled 1000 women who were between 16 and 30 weeks pregnant. Randomized
to:
1) An intervention group received expert diabetes care
including education, self-monitoring blood glucose, and
adjusted insulin therapy, and 2) A usual care
group.
Serious perinatal complications in
infants were significantly lower in the intervention group (1% vs 4%). The NNT
to prevent one serious outcome in infants = 34.
Birth weights were lower in the intervention group (less likely to have
macrosomia). No difference in rate of
hypoglycemia requiring intravenous glucose.
Women in the intervention group
gained less weight and had less risk for preeclampsia. At 3-months postpartum,
women had lower rates of depression and higher scores on quality-of-life. Rates
of caesarean deliveries were similar.
Impaired glucose tolerance and diabetes are important risk factors at the
time of conception. Primary care clinicians can serve their young adult female
patients by advising them of the risks of glucose intolerance (and excessive
weight) before and at the time of conception.
Reduced Complications and Risk Of Death.
4-9 THE EFFECT OF CARDIAC RESYNCHRONIZATION ON
MORBIDITY AND MORTALITY IN HEART FAILURE
Despite
improvements in pharmacologic treatment, many patients with heart failure (HF) have severe and persistent
symptoms. Their prognosis is poor. Such patients commonly have regions of
delayed myocardial activation (left bundle branch block), leading to cardiac
dyssynchrony.
Resynchronization
was accomplished by a pacemaker containing 3 leads (right atrium, right
ventricle, and left ventricle. This resulted in a reduction in intraventricular
mechanical delay and end-systolic volume, and an increase in the left
ventricular ejection volume. It improved symptoms and quality-of-life.
CR
substantially reduced the risk of complications and deaths among patients with HF
due to left ventricular systolic dysfunction and cardiac dyssynchrony. The
benefits were in addition to those afforded by pharmacologic therapy. Over the
study period, for every nine devices implanted, one death and 3
hospitalizations for major cardiovascular events were prevented. The reduction
in risk of death is similar to that associated with beta-blocker therapy.
Obviously
not a panacea. Experienced
consultants must be chosen with care. Patients should be aware of the high rate
of complications, and the likelihood of improvement. The greatest benefit may
be improving quality-of-life.
See illustration of lead
placement on page 1595
Enables The Ventricles
To Contract Simultaneously.
4-10 RESYNCHRONIZING
VENTRICULAR CONTRACTION IN HEART FAILURE
The
biventricular-pacemaker implantation is technically demanding. It provides
atrial-based, biventricular stimulation. Three leads are placed to pace 1) the
right atrium, the 2) right ventricle, and the 3) left ventricle The left ventricular lead is inserted into
the coronary sinus (in the right atrium) and advanced into a cardiac vein on
the lateral wall of the lateral wall of the left ventricle. This enables the
ventricles to contract simultaneously.
Complications
of insertion are more frequent than for conventional pacemaker insertion
See illustration of the
placement of the pacemaker leads on page 1595.
Primary care clinicians should be able to
advise this subset of patients if the procedure is available.
Aggressive And Effective Relief Of The Acute Pain May Reduce
The Risk Of Chronic Pain.
5-10 POSTHERPETIC PAIN: WHEN SHINGLES WANES, BUT PAIN DOES NOT
The intensity of
the acute pain shortly after onset of shingles is a robust predictor of
postherpetic neuralgia (PHN). This
leads to the tantalizing hypothesis that aggressive and effective relief of the
acute pain may prevent, or at least reduce, the risk of chronic pain.
Oral opioid
analgesics, in conjunction with antiviral drugs are likely candidates to
decrease the incidence of PHN. They are also more effective in treatment of the
acute pain. Opioids are relatively well tolerated by elderly patients.
Previous
studies have suggested that control of acute pain will reduce the severity and
prevalence of chronic pain. I believe this is an important point for primary
care. We should go all-out to control the acute pain of HZ, giving adequate
doses of opioids without restraint.
We
await availability of the live, attenuated HZ vaccine. It does prevent HZ in
elderly adults with waning cellular immunity. It lessens incidence and severity
of postherpetic neuralgia.
Reduced Incidence And Severity Of HZ
And PHN.
6-1 A VACCINE TO PREVENT HERPES ZOSTER AND
POSTHERPETIC NEURALGIA IN OLDER ADULTS.
This study
tested the hypothesis that vaccination would decrease the incidence and
severity of both HZ and PHN.
Over 38 000
subjects were randomized to: 1) a subcutaneous injection of live, attenuated
varicella-zoster vaccine, or 2) placebo. The potency of the live attenuated
A. Herpes zoster: (3 years) Vaccinated Placebo Absolute difference NNT
Confirmed cases of acute HZ 315 642 1.7% 58
Overall incidence of HZ
per 100 person-years 0.54 1.11 0.57% 175
Median duration of pain (days) 21 24
Severity of illness 141 180
(area under the curve)
Burden of illness score 2.2 5.7
B. Postherpetic
neuralgia (3 years)
Confirmed cases 27
80 0.3% 333
Persistence of pain was shorter in
the vaccinated group.
There was no evidence that the live
vaccine caused HZ.
Adverse effects were generally mild,
mainly due to local reactions.
We would expect more cases of HZ would be prevented as time progressed,
and as more individuals enter the ranks of the elderly. I asked myself—at my advanced age should I
take the vaccine? Having seen the devastating complications of zoster, I would
be more than willing to take it, even though the likelihood of prevention of HZ
over 3 years is only 1 in 58.
Questions remain:
At what age should the vaccine be recommended?
How long is the boost in immunity protective?
Is it cost-effective enough for Medicare to cover costs?
The Benefit/Harm-Cost Ratio of Vitamin B12 and Folate May Be
Very High
3-9 HOMOCYSTEINE AND FRACTURE PREVENTION
This issue of
JAMA presents evidence that an elevated homocysteine level might be associated
with brittle bones. The randomized trial of Japanese patients who had suffered
hemiplegia due to stroke compared a group given folate and B12 (effectively
lowering homocysteine levels) with a control group. The untreated group had 5
times the fracture rate as the treated group.
At baseline,
patients had low levels of serum B12 and folate, and high levels of
homocysteine. In the treatment group serum homocysteine fell by 38%; increased
by 31% in the placebo group. Serum B12 and folate levels increased in the
treatment group; fell in the placebo group.
Homocysteine is a simple
sulfur-containing amino acid. Folate and B12 are co-factors involved in its
metabolism. They facilitate conversion of homocysteine to methionine (another
sulfur-containing amino acid).
Years
ago, the genetic abnormality homocysteinuria was demonstrated to be associated
with atherosclerotic disease and osteoporosis.
Homocysteine acts as an atherogenic and thrombogenic agent. Increased
levels are associated with coronary artery disease, cerebrovascular disease,
peripheral arterial disease and deep-vein thrombosis.
A
substantial portion of the elderly in the
Supplementation
with B12 and folate reduces serum homocysteine levels.
The
benefit/harm-cost ratio of folate and B12 supplementation may be very high.
Both are relatively inexpensive and safe.
The
study did not assess vitamin D and calcium intake, although intake of both is
traditionally low in the elderly in
Practical
Pointers has abstracted a number of studies in the past 5 years which conclude
that folic acid and B12 do reduce homocysteine levels and produce clinical
benefits:
Homocysteine Levels and the Risk of
Osteoporotic Fractures May 2004 [5-10]
Associated
with reduced risk of congestive heart failure
March 2003 [3-14]
Observing
a reduction in dementia and Alzheimer’s disease February 2002 [2-10]
Reducing
risk of major cardiac events and restenosis after PTCA November 2001 [11-11]
Causes More Cancer Than It Prevents
5-7 ENDOMETRIAL CANCER AND HORMONE REPLACEMENT
THERAPY IN THE MILLION WOMEN STUDY
Estrogen-only hormone-replacement
therapy (HRT) increases the risk of
endometrial cancer (EC). To
counteract this effect, many postmenopausal women who have not had a
hysterectomy use combined HRT (progestagen +
estrogen). The addition of progestagen attenuates or even reverses the
estrogen-associated increase in EC.
This large study assessed the
relation between different types of HRT and incidence of EC.
Relative risk of EC compared with
never-users:
Continuous combined HRT (progestagen
daily + estrogen daily—RR =
0.71 (A reduction in risk.)
Combined cyclic HRT (progestagen 10
to 14 days/month—RR = 1.05 (No significant alteration.)
Estrogen alone—RR = 1.45 (Increased
risk.)
But the benefit in lowering risk of
EC was greatly offset by a rise in breast cancer.
Incidence rates for endometrial
cancer and breast cancer per 1000 women over 5 years:
Continuous combined Cyclic
combined Estrogen alone Never users
Endometrial
cancer 2.0 3.0 4.9 3.0
Breast
cancer 29 28 18 14
Thus, although continuous combined
HRT reduced risk of endometrial cancer by 1 in 1000 over 5 years, it was
associated with 15 more breast cancers. This is an increase in total cancers of
14 per 1000. Estrogen alone was associated with a lower risk (4 total cancers
per 1000 women over 5 years).
Combined estrogen-progestagen
causes a greater increase in breast cancer than a reduction in EC. The net
effect is an increase in total cancer
risk with use of HRT, especially combined HRT.
Progestagens, not estrogens, are the main factor increasing risk of BC.
Just think—another extraordinary sea change in clinical application. For
decades standard HRT practice insisted that, for women with a uterus, a
progestagen be added to estrogen. This on the pain of being
accused of malpractice.
Primary Hyperparathyroidism Does Not
Progress In Most Patients. “Most Have No Symptoms”
4-8 A 64-YEAR OLD WOMAN
WITH PRIMARY HYPERPARATHYROIDISM
This
“Clinical Crossroads” conference presents the history of Mrs. Q, a 64-year old
woman with mild hypercalcemia over 7 years. Her serum calcium has varied from
time to time (10.1 to 11.3 mg/dL; normal = 9.0 – 10.5 mg/dL). Her parathyroid
hormone level was 102 pg/mL (normal = 10 – 60 pg/mL); phosphate level = 3.4
mg/dL;
albumin level = 4.1 g/dL
She
was asymptomatic; never had any fracture or renal stone. No depression or mood
swings. She did not take vitamin D or calcium. Her bone mineral density had
decreased by 7% at the spine and by 5% at the femoral neck. 24 hour calcium
excretion = 226 mg. Creatinine clearance normal.
A
sestamibi scan revealed a localized increased uptake in the lower pole of the
thyroid.
The
consultant parathyroid surgeon concurred that the patient had mild chronic
primary hyperparathyroidism.
How
to proceed?
The
article discusses epidemiology, pathophysiology, evaluation, end-organ effects,
progression of the disease, effects on general
well-being, surgical treatment, and recommendations of the National Institutes
of Health for surgery.
Our understanding of the
natural history of primary hyperparathyroidism has been clarified and expanded
over the years.
The article describes
several points which were new to me:
Hyperparathyroidism in
all its forms is characterized by a re-setting of the activity of the
parathyroid glands to maintain a calcium level above normal range. A new
balance is reached wherein the parathyroid hormone (PTH) excretion is increased
to maintain the serum calcium at a higher than normal level. The higher calcium
level restrains the gland and maintains its secretion at a higher set
level. In all other forms of
hypercalcemia PTH is suppressed.
Prospective studies
over 10 years have reported that primary hyperparathyroidism does not progress
in most patients. “The stability of most cases of primary hyperparathyroidism
is surprising, considering the neoplastic nature of the disorder.” It may be
related to the previously mentioned set-point for secretion of PTH. (Secretion of the adenoma is suppressed by
the elevated serum calcium levels.) The
adenoma may grow until the serum calcium set-point is reached. Then secretion
of PTH secretion remains steady and the tumor stops growing.
A new approach,
minimally invasive parathyroidectomy, requires preoperative localization of the
adenoma by scanning with Technicium Tc99m-labeled sestamibi. If an adenoma is
located, a limited incision may be made. Morbidity is lowered, operating time
shortened, and hospital stay reduced.
If you practice primary care long
enough you will unexpectedly encounter a patient with primary hyperparathyroidism.
Most are identified by a chemical screen, which reveals high serum calcium.
I believe
many primary care clinicians would inform this patient:
1) The
disease will not go away. It may progress and lead to increased bone loss over time.
2) You have
already undergone 7 years of testing, worry, inconvenience, and expense.
3) Surgery
will cure you and end all these concerns. The minimally invasive technique is
safe. Recovery is rapid.
Primary care
clinicians choose your surgical consultant carefully.
If Confirmed, This Represents An Enormous Public Health
Benefit.
1-4 FOLATE INTAKE AND THE RISK OF HYPERTENSION AMONG U.S. WOMEN
Oral folic acid
supplementation improves endothelial function. Folate may have beneficial
effects on blood pressure by increasing nitric oxide synthesis in endothelial
cells, and by reducing plasma homocysteine levels. (Homocysteine by itself can
cause endothelial cell injury.)
This study
assessed the association of folate intake with incident hypertension in 2 large
groups of women.
Younger women
(mean age 36 at baseline):
Identified 7373
incident cases of hypertension (8%) over 8 years.
Subjects whose daily
consumption was at least 1000 ug of total folate (diet + supplement) had a relative
risk of developing hypertension of 0.54 compared with women who consumed less
than 200 ug daily.
Absolute risk reduction of incident
hypertension was about 8 cases per 1000 person-years.
Older women
(mean age 55 at baseline):
Identified 12347 incident cases of hypertension (19%) over 8 years.
Relative
risk of hypertension (1000 ug folate daily vs
less than 200 ug) = 0.82.
Absolute
risk reduction of incident hypertension was about 6 per 1000 person-years.
The most significant relationship was
associated with supplemental (not dietary) folate intake.
(Bioavailability
of supplemental folate is twice that of food folate.)
Younger women
achieved the most benefit. Younger women whose intake was at least 1000 ug
experienced 1/3 the risk of developing hypertension over 8 years. (Ie, start supplementation early. RTJ)
High intake of
folate was associated with a decreased risk of incident hypertension,
especially in younger women. Supplemental folate was independently beneficial.
If confirmed as true, this has enormous
public health benefit.
The
benefits of folate extend to prevention of spina bifida and coronary heart
disease. The benefit/harm-cost ratio is very high.
A Practical Definition Of
Hypertension: The Value Of BP Below Which No Further Benefit Of Lowering The BP
Can Be Demonstrated
3-3 HYPERTENSION—TIME TO MOVE ON
In
view of the continuous associations
between BP and cardiovascular disease risks, the value of categorical systems
for classifying BP is questionable. Such categorical systems provide little
useful information about an individual’s
risk of actually developing a blood-pressure-related cardiovascular
disease. Most guidelines acknowledge
that risks are determined by many factors and not by BP alone.
A practical definition of
hypertension is the value of BP below which no further benefit of lowering the
BP can be demonstrated. There is now compelling epidemiological evidence of
continuous associations between usual BP values down to about 115/75 and risks
of major cardiovascular disease. Non-hypertensive individuals with multiple
risk factors or a history of cardiovascular disease will often be at higher absolute risk of BP-related
cardiovascular events than hypertensive patients without other risk factors.
“So why do we persist with this focus
on the treatment of hypertension (defined arbitrarily) rather than the prevention
of blood-pressure-related diseases?”
This reinforces the argument
presented in the preceding article—risk factors are additive and should not be
considered alone.
Neither Amlodipine
Nor Lisinopril Was
This
subset of the study assessed outcomes in the entire group ( n
= 33 000) for renal outcomes. The methods used were identical to those in the
study of blacks. Chlorthalidone, lisinopril, and amlodipine were used
separately as first line therapy.
In
both diabetic and non-diabetic participants, the 6-year rate of ESRD for those
assigned to chlorthalidone was no different from those assigned to lisinopril.
The benefits of ACE inhibitors (and angiotensin blockers) have been attributed
to their effects on the renin-angiotensin system and their unique anti-proteinuric
effects. Epidemiological studies have demonstrated a strong association between
BP and ESRD outcomes. There was, however little difference in BP between the
chlorthalidone and lisinopril groups.
What is the message for
primary care clinicians? Fortunately, we
are not limited to an either-or choice of therapy as in the trial. Most
high-risk hypertensive patients (with and without diabetes) will require two or
three drugs to reduce BP as much as possible. A combination of a diuretic, an
ACE, and a calcium blocker would be appropriate.. The
diuretic should not be omitted. Addition of a beta-blocker should be considered
in some patients.
Thiazides the Drugs of First Choice
for Blacks as well as Whites.
Blacks have the
highest morbidity and mortality from hypertension of any population group in
the
This study asks
if the benefits of thiazide diuretic therapy (chlorthalidone) compared with an
ACE –inhibitor (lisinopril) and Calcium blocker (amlodipine) extended to black
patients.
In blacks,
neither the ACE nor the CB was more effective than the thiazide diuretic in
preventing the primary outcome of fatal CVD + non-fatal-MI, or any other major
cardiovascular or renal outcome.
Chlorthalidone
was superior to ACE and CB in reducing incidence of heart failure.
Chlorthalidone
was associated with a lower incidence of stroke than lisinopril.
Much of the
comparative benefit may have been due to the greater reduction in systolic BP
associated with chlorthalidone.
“Thiazide-type
diuretics remain the drugs of choice for initial therapy of hypertension in
both black and non-black hypertensive patients.”
Using
a diuretic as first-line therapy in both blacks and whites is associated with
considerably lower costs over the years.
Costs;
Chlorthalidone and hydrochlorothiazide cost 9 to 12
cents a day
Prinivil 53 cents a day ; Norvasc $1.40 a day.
“Hypertensive End-Organ Damage Begins With A BP Below 140/90.”
Establishing
a detrimental effect of lesser degrees of BP elevation on the kidneys is
difficult because kidney disease itself can elevate BP. This study asks: What is the importance of hypertension as a
risk factor for ESRD?
A
graded association between baseline BP and risk of ESRD existed among subjects
without clinical evidence of kidney disease at baseline. Even relatively modest
elevations of BP were associated with an increased risk of ESRD. “Hypertensive
end-organ damage begins with a BP below 140/90.”
At
any given level of BP there was a much higher risk of ESRD among blacks and
patients with diabetes. Again demonstrating that risk
of disease follow a linear pattern. There is no “normal” BP cut point.
Extra vigilance is required
for black patients and for those with diabetes.
In Modestly Overweight Persons, Reduction In Weight May Lower
Risk Of Developing Hypertension.
6-11 WEIGHT
LOSS IN OVERWEIGHT ADULTS AND THE LONG-TERM RISK OF HYPERTENSION: The Framingham Study
Obesity is
associated with higher levels of insulin resistance, hyperinsulinemia, rises in
cardiac output, increases in cholesterol and triglycerides, and increased
sympathetic nervous system activity. Most of these changes have been associated
with increases in BP. “In recent years, there has been a great deal of focus on
the roles of hyperinsulinemia and insulin resistance in the development of
hypertension.”
The goal of this
study was to estimate the effects of both the amount on weight loss and the
persistence of weight loss on the risk of incident hypertension among already
obese adults. (Primary
prevention.)
After multiple
adjustments, weight loss of 6.8 kg (18 pounds) or more led to a 28% reduction
in risk of developing long-term hypertension in younger subjects (mean age 27)
, and a 37% reduction in older subjects (mean age 52).
If the weight loss was sustained over the
years, the risks of developing hypertension were reduced by 22% and
26%.
“The results of
this study suggest that at least 15% of the cases of hypertension in overweight
middle-aged adults and 22% of the cases occurring in overweight older adults
could be prevented by a modest amount of sustained weight loss.”
Overweight
+ hyperinsulinism + dyslipidemia + hypertension = a common and deadly combination
No Evidence Of Superiority For
Treatment With A Calcium Channel-Blocker, Or An ACE Inhibitor Compared With A
Thiazide-Type Diuretic
The Antihypertensive and Lipid-lowering Treatment to prevent
Heart Attack Trial (ALLHAT)
This
is one of a series of articles reported by the ALLHAT group.
There was no
evidence of superiority for treatment with a calcium channel-blocker, or an ACE
inhibitor compared with a thiazide-type diuretic during first-step
antihypertension therapy in DM, IFG, or NG.
Most
hypertensive patients with DM or IFG or impaired glucose tolerance, I believe,
would receive more than one antihypertension drug. Many clinicians would use a
combination of an ACE inhibitor and a diuretic.. Any
combination should include a thiazide.
The abstract of this study is brief since I already abstracted similar
studies by the same ALLHAT group:
A. JAMA December 18, 2002; 2981-97 presented the original
ALLHAT study. (See Practical Pointers December 2002 [12-1]) The study compared the same 3 drugs in
similar patients with hypertension and at least one additional risk factor
(high-risk). Conclusion: “Thiazide-type diuretics should be considered
first for pharmacological therapy in patients with hypertension.” They are unsurpassed
in lowering BP, reducing clinical events, and in tolerability. They are much
less costly. Since many patients with hypertension will require more than one
drug to control their BP, it is reasonable to infer that a diuretic should be
included in all multidrug regimens.
B. JAMA April 6, 2005;
293: 1595-1608 (See Practical Pointers April 2005 [4-2]) “Thiazide-type
diuretics remain the drugs of first choice for initial therapy of hypertension
in both black and non-black hypertensive patients.”
C. Archives Int Med April 25, 2005;
165: 936-46. “Renal Outcomes in
High-Risk Hypertensive Patients with an Angiotensin-Converting
Enzyme Inhibitor or a Calcium Channel Blocker vs
Diuretic.”
In hypertensive patients with reduced glomerular filtration rate, neither
amlodipine nor lisinopril was superior to chlorthalidone
in reducing the rate of development of end-stage renal disease or a 50% or
greater reduction of glomerular filtration rate.
See
also:
NEJM December 30, 2004; 351: 2805-16 (Practical Pointers December 2004
[12-2] ) “Association between
Cardiovascular Outcomes and Antihypertensive Treatment in Older Women”
Conclusion: Monotherapy
with diuretics was equally or more effective than other monotherapies. The
combination of diuretics + beta-blockers was superior to, or equally effective
as, other combinations.
When To Intervene? How To Intervene?
6-7
THRESHOLDS FOR NORMAL BLOOD PRESSURE AND SERUM
CHOLESTEROL.
In 2003, European guidelines
suggested a BP of above 140/90, and a cholesterol
above 5 mmol/L (193 mg/dL) as the appropriate thresholds for intervention. “The
bottom line is that the doctor is expected to inform the patient that these
measurements mean that he or she is at increased cardiovascular risk regardless
of the management proposed. In other
words, a disease label is to be attached to the patient.”
In
The potential benefits for treated
patients become less at lower risk levels. The number needed to treat is
increased. The rates of adverse effects (of drug treatment) remain the same.
Adverse effects tend to be under-reported and under-published.
Certainly, experts who developed these guidelines did not suggest that
all persons with BP and cholesterol levels above these cut-points should be
treated with drugs.
I believe however, that all should be treated with judicious advice about
changing in lifestyle. This will apply to almost all persons in the
I do not believe life-style advice will be interpreted as a labeling of
disease. There are few if any adverse effects of lifestyle changes.
Effectiveness is established. The benefit/harm-cost ratio is very low.
The task of educating patients about healthy lifestyles and getting them
to adopt them is daunting, and in the main unsuccessful. We should not be
deterred from trying. This includes primary care clinicians’ adopting a healthy
lifestyle themselves.
Who should be treated with drugs?—patients who are indeed at high risk.
The definition of “high risk” depends not only on the number or risk factors
present and their levels, but also on the individual patient’s assessment of
his own risk. Patients must be convinced of the benefits of drug therapy; must
understand that drug therapy is long-term, expensive, and carries risks of its
own.
2-1 DOES THIS PATIENT HAVE INFLUENZA?
This systematic review deals chiefly with precision and accuracy of
diagnosis of flu by symptoms and signs. It leads to other publications by the
CDC which are helpful in diagnosis, treatment, and
prophylaxis of flu
Diagnosis by signs and symptoms: “Fever, headache, myalgias and cough are the
classic symptoms that physicians associate with influenza. Unfortunately, these
symptoms are frequently seen in patients presenting with other infections
during influenza season, making the clinical diagnosis of influenza a challenge
to the primary care physician.”
Epidemiology; Clinician’s knowledge of the current epidemiological
status of flu in the community is basic to accurately estimate the probability
of influenza in a given patient.
Laboratory diagnosis: Rapid diagnostic tests are now available
for office use. Results are available within 30 minutes: The tests require swabs of the nasopharynx.
The sensitivity (% of patients with flu who have a positive test) and
specificity (the % of patients who do not have flu who have a negative test.)
vary. Two commercial tests have waivers from the Clinical Laboratory
Improvement Amendments, and can be used in office settings.
Treatment: Four drugs are approved for early
treatment—oseltamivir (Tamiflu);
zanamivir (Relenza); amantadine (Symmetrel; Generic); and rimantadine (Flumadine; generic). Tamiflu is
effective against both A and B, and can be given by mouth.
Test and treat or treat empirically
without testing:
Depending on
the acuity of the illness, vaccination status, and presence of co-morbid
conditions, some physicians might choose to treat empirically with an antiviral
drug. Empirical treatment may be favored because the test may be a false
negative.
Decision must be
based on epidemiologic estimates of the likelihood of the infection in the
community. The decision is sensitive to prior vaccination status.
Physicians
who were provided with rapid test results prescribed fewer antibiotics, ordered
fewer lab studies and chest X-rays, and kept the patient in the emergency
department for shorter periods of time and generated fewer charges.
Chemoprophylaxis:
Three drugs are approved—amantadine, rimantadine, and oseltamivir.
CDC
has, in the past, encouraged use of amantadine and rimanatadine for chemoprophylaxis.
Oseltamivir
(Tamiflu) may be a better choice since it
covers both A and B. It is well tolerated. Less than 1% of patients experience nausea and vomiting
which leads to withdrawal. The
Prophylaxis
is indicated for persons at high risk of serious complications and immunosuppressed
patients including those in institutions.
Vaccinated as well as unvaccinated immunosuppressed residents in institutions where an outbreak occurs
should receive chemoprophylaxis for the duration of the outbreak.
If non-immunosuppressed patients can be
vaccinated, the prophylaxis may be continued for 2 weeks until immunity
develops.
A Circumference Under 100 Cm Rules Out Insulin Resistance And
Hyper-Insulinemia.
6-3 USE OF WAIST CIRCUMFERENCE TO PREDICT
INSULIN RESISTANCE
This study
assessed how effectively different anthropometric markers used in clinical
practice can predict insulin sensitivity. The authors suggest abdominal
circumference is the most powerful independent predictor to rule out insulin
resistance.
Determined height, weight, and waist circumference (midway between
lateral lower ribs and iliac crest). Also determined results from
analyses of plasma for glucose, insulin, and lipid concentrations. Used a
homoeostasis index as a measure of insulin sensitivity [plasma glucose (mol/L) X plasma insulin
(mU/L)/22.5]. A score of 4.0 and greater
was defined as insulin resistance.
Using 100 cm as
a test, the authors determined the sensitivity to diagnose insulin resistance
was between 94-98%; and the specificity was between 61-63%. The positive
predictive values of the test were 61% for men and 42% for women. The negative
predictive value of the test was 98% in men and 97% in women. A waist
circumference under 100 cm was therefore a strong independent predictor in ruling out insulin resistance.
Waist
circumference is a simple tool to exclude
insulin resistance. If the patient has a circumference under
100 cm (40 inches), he or she is very unlikely
to have insulin resistance and hyper-insulinemia. Circumferences above 100 cm
may, or may not, be related to insulin resistance.
I
found this short article provocative. The results require confirmation.
Abdominal girth is an important risk factor for the metabolic syndrome and
cardiovascular disease .
Warfarin Provided No Benefit Over Aspirin. Was
Associated With More Adverse Effects.
3-7 COMPARISON OF WARFARIN AND ASPIRIN FOR
SYMPTOMATIC INTRACRANIAL STENOSIS.
Randomized, double-blind multicenter
(59 sites) trial entered over 550 patients (mean age 63). All had experienced a
TIA or a non-disabling stroke caused by angiographically verified 50% to 99%
stenosis of a major intracranial artery (internal carotid, middle cerebral,
vertebral, or basilar).
Randomized to: 1) warfarin—target INR of 2.0 to 3.0, or 2)
aspirin 650 mg twice daily.
Warfarin provided no benefit over
aspirin. It was associated with significantly higher rates of adverse events.
“Aspirin should be used in preference to warfarin for patients with
intracranial arterial stenosis.”
This is a good example of a pragmatic (real
world of practice) trial. Difficulty in control of warfarin dosage may have
been the cause of its lack of benefit.
Combinations of A Statin, A
Beta-Blocker, and Aspirin Improve Survival in High-Risk Patients
5-2 EFFECT OF COMBINATIONS OF DRUGS ON ALL-CAUSE
MORTALITY IN PATIENTS WITH ISCHEMIC HEART DISEASE
This case-control study assessed the
effect of combinations of drugs (statins, aspirin, beta-blockers and
angiotensin converting enzyme inhibitors [ACE])
in the secondary prevention of
all-cause mortality in patients with ischemic heart disease.
All-cause mortality: Adjusted
odds ratio (controls/cases)
Statins alone 0.53
Aspirin alone 0.59
ACE alone 0.80
Beta-blocker alone 0.81
Combined statin, aspirin &
beta-blocker 0.17
Combined statin, aspirin,
beta-blocker, and ACE 0.25
In this secondary prevention study,
combinations of statins, aspirin, and beta-blockers improved survival in high-risk
patients with IHD.
Millions of Americans are now using multiple drugs for primary, as well
as secondary prevention. This includes drugs for hypertension [thiazides,
beta-blockers, ACE inhibitors], statins for
dyslipidemia, and low-dose aspirin. The absolute benefit will be lower than
when used for secondary prevention.
We could include other interventions for both primary and secondary
prevention: weight control; physical fitness; modest daily intake of alcohol.
“May Lead To Treatment Which Slows
Disease Progress”
4-14 GENE DISCOVERY
PROVIDES CLUES TO CAUSE OF AGE-RELATED MACULAR DEGENERATION
A gene variant
may be responsible for about half of the 15 million cases of AMD in the
Individuals who
possess a certain variant of the CFH gene are at increased risk of AMD. The
protein [tyrosine replaced by histidine] encoded by the variant fails to bind
to receptors on cells on the retina and surrounding blood vessels. The
protective effect of normal CFH is lost. This leads to increased inflammation
in the retina and choroid.
Discovery of this variant may lead to treatment which slows disease
progress. A modest slow-down would be sufficient to preserve a patient’s
vision for the rest of his life.
While
not a practical point at this time, I felt the “News” was provocative enough to
abstract.
Associated with longer
survival.
4-4 MODIFIED MEDITERRANEAN DIET AND SURVIVAL
The
Mediterranean diet (MD) is characterized
by a high intake of vegetables, legumes, fruits, and cereals (largely
unrefined); a moderate to high intake of fish; a low intake of saturated fats;
a high intake of unsaturated fats (particularly olive oil); low to moderate
dairy products; a low intake of meat; and a modest intake of ethanol, mostly as
wine.
This
study examined whether adherence to a modified MD (poly-unsaturated fats
substituted for mono-unsaturates) was associated with longer life expectancy
among elderly Europeans.
Means
scores on the 10-point MD scale varied considerably between countries.
An
increase in this modified MD score was associated with lower overall mortality.
A two-unit increment corresponded to a reduction on 8% in mortality.
I believe the modification
(substituting poly-unsaturated fats for mono-unsaturated fat) is a clinically
important point. Poly-fats are more accessible in our culture than mono-fats.
The Cost Of Treating
Patients Who Benefit + Those Who Do Not Benefit.
4-6 “MONEY” NEEDED TO TREAT (MNT)
The
costs of treatment (money needed to treat to benefit one patient) can be easily
calculated from analysis of trials which report the NNT(to
benefit one patient over a given duration of therapy) in absolute terms. And by determining the cost of the drug.
A
trial reported in NEJM April 7, 2005 “Intensive Lipid Lowering with
Atorvastatin in Patients with Stable Coronary Disease” compared use of 80 mg
the statin drug atorvastatin (Lipitor)
with 10 mg. The LDL-cholesterol was lowered to a greater extent in the 80 mg
group.
Over
5 years, major cardiac events occurred in 8.7% in the 80 mg group, and 10.9% in
the 10 mg group Absolute difference = 2.2%; NNT(over 5 years to benefit one
patient) = 45. Thus, 44 would be treated needlessly.
Based on the NNT (benefit) + the NNT(needlessly), the total cost of the 80 mg dose (44 + 1) = $65 700
Conversely,
patients may be told that they will spend $1460 over 5 years to achieve a one
in 45 chance of benefit.
The Clinical Hallmark Is Fatigable
Muscle Weakness Which Improves With Rest and Application Of
Cold
4-11 DOES THIS PATIENT HAVE MYASTHENIA GRAVIS?
This
article reviews: anatomical and physiological
origins of symptoms and signs; how to elicit symptoms and signs; anticholinesterase tests; and analysis of
articles reviewed.
The
approaches to diagnosis and treatment have evolved over the years. Testing now
includes the ice pack
test, the rest test, the sleep test, and the peek sign.
“Fluctuating
weakness that worsens with exertion and improves with rest or with application
of ice or cold is never normal.” The fluctuation is dramatic and occurs
rapidly.
Bear
in mind that the initial fluctuating weakness of MG may become fixed over time
if severe enough.
Certain historical features (speech becoming unintelligible after
prolonged periods) of signs (peek test) maybe useful in diagnosis. Their
absence does not rule it out.
The
ice test, sleep test, and response to anticholinesterase agents are useful in
confirming the diagnosis. A positive
test result should prompt proceeding with acetylcholine receptor antibody
testing and specialist referral.
The authors did not mention a common associated abnormality—enlargement
of the thymus. This is frequent enough, I believe, to warrant imaging in
suspected cases of MG.
The patient with MG, on
first presentation, should present suggestive symptoms and signs. Speaking from
personal experience, it is embarrassing to miss the diagnosis.
Addition of Clopidogrel Improved Patency of The Affected Artery and Reduced Ischemic Complications.
A substantial proportion of patients
receiving fibrinolytic therapy for MI with ST-segment elevation have inadequate
reperfusion or re-occlusion of the infarct-related artery. Aspirin
significantly improves outcomes. But, aspirin is a relatively weak antiplatelet
agent. It has limitations. It irreversibly inhibits cyclo-oxygenase in
platelets thereby inhibiting synthesis of thromboxane, a powerful promoter of
platelet activation. It exerts no effect on thromboxane-independent mediators
of platelet activation. Up to 30% of persons with coronary artery disease are
relatively resistant or unresponsive to aspirin.
Clopidogrel (Plavix) acts differently from aspirin in inhibiting activation and
aggregation of platelets. Does addition of clopidogrel benefit patients with
acute ST-segment elevation MI who are receiving fibrinolysis and aspirin?
The short-time study enrolled over
3400 patients (mean age 57) who presented within 12 hours after onset of an
acute ST-segment elevation MI. Randomized to: 1) clopidogrel (300 mg loading
dose followed by 75 mg once daily), or 2) placebo.
Over a period of
about a week, the addition of
clopidogrel improved patency of the affected artery and reduced ischemic
complications and death.
Treatment was not associated with an
increased rate of major bleeding or intracranial hemorrhage.
Plavix has been extensively advertised to
the public for ongoing use in patients with CVD. It is expensive. A 75 mg
tablet costs almost $4.
I
believe primary care clinicians may provide a meaningful advanced therapeutic
measure to a patient presenting to the office with an acute MI. While transfer
to the hospital is arranged, the patient may be given:
1) full dose aspirin (325 mg); 2) clopidogrel
(300 mg); 3) a statin drug; and 4) a beta-blocker. A few packets containing
these drugs may be kept handy. .
The Combination Was Associated With Significantly Less
Pain-Related Interference with Mood, And Higher Scores for Vitality and Social
Functioning
3-4 MORPHINE,
GABAPENTIN, OR THEIR COMBINATION FOR NEUROPATHIC PAIN
This study assessed the effectiveness
of a combination of morphine + gabapentin vs
either alone and placebo for pain due to diabetic neuropathy and post-herpes
zoster neuralgia.
Treatment with a combination of
morphine + gabapentin resulted in greater relief of pain than treatment with
either alone.
Baseline Placebo Gabapentin Morphine Morphine + gabapentin
Mean daily pain scores 5.7 4.5 4.2 3.7 3.06
On a scale of 1 to 10
McGill Pain Questionnaire 18.9 4.4 10.7 10.7 7.5
On a scale of 0 to 45
The maximum doses of morphine and
gabapentin were lower with the combination than for each given separately.
The
combination was associated with significantly less pain-related interference
with mood, and higher scores for vitality and social functioning. The combination was also associated with
improvement in depression as measured by the Beck Depression Inventory.
This may bring considerable relief to some patients with very disturbing
pain.
Gabapentin(Neurontin) is an analogue of butyric acid. It modulates
calcium channel subunits thought to be important in neuropathic pain. It has
both analgesic and anti-convulsant action and is approved for treatment of
partial seizure epilepsy and post-herpetic neuralgia.
Gabapentin and morphine have
mechanically distinct analgesic actions The
combination may result in synergistic or additive pain relief at lower doses
and with fewer side effects.
Repeated administration of gabapentin does not lead to tolerance.
Too Often, Large Numbers Of Patients
Are Being Treated Without Benefit.
4-5 NUMBERS NEEDED TO TREAT (NEEDLESSLY?)
The
authors suggest a new index NNT(needlessly) to
complement NNT(benefit). The higher the number, the greater
the treatment burden.
For
example, if the absolute difference between drug compared to placebo is 2% over
5 years, the NNT(benefit one patient) = 50. Of these,
only one of 50 is benefited; 49 are treated (needlessly).
NNT(benefit) puts the emphasis on the positive side. But it
tends to obscure the reality, that, too often, large numbers of patients are
being treated without benefit.
The
authors believe the new parameter will remind us that we should not be
complacent about our inability to better identify patients who will benefit
from our well-meaning interventions.
NNT(needlessly) may also help patients decide on their
course of therapy.
This is a good illustration
of the uncertainty principle of therapeutics, which is related to all
treatments. We cannot judge beforehand which patients will benefit and which
ones will be treated unnecessarily. The numbers in the latter will almost
always be higher than the former.
The number needed to harm [NNT(harm)] is another helpful index. It can be easily
calculated from data presented in trials. Usually, the older a patient becomes
the greater the NNT(harm).
We might also consider the
“Money Needed to Treat” (MNT). (Ie, the cost of a drug to
benefit one patient + the cost of treating many patients needlessly. See
the following. RTJ
Adherence was Poor.
Those Who Adhered for One Year Lost Weight
This
study assessed adherence rates and effectiveness of 4 diets in producing weight
loss and reducing cardiac risk factors:
1. Atkins Low carbohydrate—20 g
carbohydrate daily
2. Zone High protein, low
glycemic load
3. Weight Watchers Balanced diet—total daily
”points” in a range determined by current weight (Aimed for 24 to 32 points daily.)
4. Ornish Low fat, vegetarian
diet containing 10% of calories as fat.
About half of the subjects in each
group failed to complete the 1-year course. The most common reasons were “too
hard to follow” and “not yielding enough weight loss”. Adherence was
particularly low for Atkins and Ornish.
At 1 year, completers lost more than
those who failed to complete
( - 3. 9 kg for Atkins and -6.6 kg for Ornish)
Each diet significantly reduced
LDL/HDL-cholesterol ratio by about 10%. The Atkins diet did not lower
LDL-cholesterol significantly. The Ornish diet did not increase the
HDL-cholesterol. No diet significantly altered triglyceride levels. Reductions
of total cholesterol, C-reactive protein, and insulin levels were significantly
associated with the degree of weight loss.
Under realistic conditions a variety
of popular diets can reduce weight and several cardiac risk factors. But only
about half of the subjects in this study sustained a high adherence level.
The problem is not the diet, it is the patient’s
inability to follow it. Recidivism would be higher still at 5 or 10 years. The bloom seems to be coming off the Atkins
diet.
The authors suggest that one way to improve dietary adherence in clinical
practice may be to use a broad spectrum of diet options to better match
individual patient’s food preferences, lifestyles, and cardiovascular risk
factors. They suspect adherence would have been better if subjects had been
given the option to choose their diet.
I wonder—would switching from one type of diet
to another every few months increase compliance?
In Modestly Overweight Persons, Reduction In Weight May Lower
Risk Of Developing Hypertension.
6-11 WEIGHT LOSS IN OVERWEIGHT ADULTS AND THE
LONG-TERM RISK OF HYPERTENSION: The
Framingham Study
Obesity is
associated with higher levels of insulin resistance, hyperinsulinemia, rises in
cardiac output, increases in cholesterol and triglycerides, and increased
sympathetic nervous system activity. Most of these changes have been associated
with increases in BP. “In recent years, there has been a great deal of focus on
the roles of hyperinsulinemia and insulin resistance in the development of
hypertension.”
The goal of this
study was to estimate the effects of both the amount on weight loss and the
persistence of weight loss on the risk of incident hypertension among already
obese adults. (Primary
prevention.)
After multiple
adjustments, weight loss of 6.8 kg (18 pounds) or more led to a 28% reduction
in risk of developing long-term hypertension in younger subjects (mean age 27)
, and a 37% reduction in older subjects (mean age 52).
If the weight loss was sustained over
the years, the risks of developing hypertension were reduced by 22% and 26%.
“The results of
this study suggest that at least 15% of the cases of hypertension in overweight
middle-aged adults and 22% of the cases occurring in overweight older adults
could be prevented by a modest amount of sustained weight loss.”
Overweight
+ hyperinsulinism + dyslipidemia + hypertension = a common and deadly
combination
Likely To Produce Clinically
Important Pain Relief.
Effective pain
relief in these patients is difficult to achieve. Use of opioids is controversial.
This is in part because studies have been small, have yielded equivocal
results, and have not established long-term efficacy and safety. There have
been concerns about adverse effects:
potential for abuse and addiction, hormonal abnormalities, dysfunction
of the immune system, and paradoxical hyperalgesia.
This systematic
review assessed the efficacy and safety of opioids for treatment of NP.
Opioid treatment
for 1 to 8 weeks had a beneficial effect over placebo for spontaneous
neuropathic pain. The magnitude of this opioid effect was nearly a 14-point
difference in pain intensity at study end compared with placebo. Is an average decline of 14 points on a
100-point scale meaningful to patients? The mean initial pain intensity ranged
from 46 to 69. A 14-point difference corresponds to a 20% to 30% reduction in
pain.
The trial did
not address issues of addiction. It is reasonable to assume that the studies
did not include individuals who might be potential abusers.
The most common
adverse effects were nausea, constipation, drowsiness, vomiting, and dizziness.
(NNT to harm one patient = 4 to 7.)
I
believe primary care clinicians underuse opioids for patients with non-cancer
pain. Fears of addiction have been overemphasized.
Should Beta-Lactams be the Antibiotics of Initial Choice in
Adults with Community-Acquired Pneumonia?
One of the
barriers to better define treatment of community-acquired pneumonia (C-AP) is the inability to accurately
determine which organisms might be the cause. Streptococcus pneumoniae has long been considered a common
pathogen. It is now apparent that other
organisms are causative—Mycoplasma
pneumoniae, Chlamydia pneumoniae, and Legionella species. Their major
distinguishing feature is a lack of response to beta-lactam antibiotics.
This meta-analysis
compared the efficacy of beta-lactam antibiotics (eg. penicillin; amoxicillin)
with antibiotics active against atypical pathogens in adults with C-AP: 7 different fluoroquinolones (eg,
levofloxacin); 2 macrolides (eg, erythromycin;
azithromycin).
The study
assessed only the necessity for coverage of atypical pathogens in the initial management of community-acquired
pneumonia.
“Data from our
analysis do not support the need for antibiotics that possess specific activity
against atypical pathogens in the initial
managements of adults with mild-to-moderate community-acquired pneumonia.”
“We suggest that
the role of M pneumoniae and C pneumoniae in community-acquired
pneumonia may have been overplayed.”
There was no evidence that specific therapy is required for M pneumoniae
and C pneumoniae. Legionella infections do require specific therapy.
Antibiotic
treatment should always be reassessed in any patient who shows signs of
deterioration or failure to improve.
“Beta-lactams
should remain the antibiotics of initial
choice in adults with community-acquired pneumonia.”
This
approach to therapy reflects the British view. It remains controversial. When I
was abstracting the study, I wondered if beta-lactam therapy would be generally
acceptable in the
The
article did not mention the increasing resistance of S pneumoniae to
beta-lactams (as well as many other antibiotics including erythromycin).
Primary care clinicians should be aware of the likelihood of penicillin
resistance in their community. There are now reports that some strains of S
pneumoniae are susceptible only to vancomycin.
POWER AND AUTHORITY IN MEDICINE
Physician’s Power Can be Enhanced, Diminished, Used
Well or
1-10 CONSENT OR OBEDIENCE? Power and Authority in Medicine
This
essay considers the role of
inappropriate obedience as a source of abuse in the teaching hospital and the
effect of obedience on patients’ autonomy and consent.
Patients
provide consent not only about big issues, but, in the course of an illness,
sick patients consent innumerable times to interventions that they would rather
not undergo.
Serious
illness is marked by losses of normal function in many dimensions of existence,
including the ability to
reason and to act (without which “autonomy” loses meaning). Sick
patients do not reason their way to decisions based on their appraisals of the
relevant information, but because an authority helps them to decide.
A
power comes from the hospital setting and the trappings of medical authority.
“Such power can be enhanced, diminished, used well or ill, but it cannot be
disowned.”
Bearing
in mind the effect of sickness on function, we should accept the propensity of
sick patients to seek our approbation, celebrate our expertise, and acknowledge
the legitimacy of our authority by doing as they think we wish. These
tendencies present us with difficult responsibilities.
“The
biggest thief of autonomy is sickness.”
I enjoyed this thoughtful
essay.
We live in a world in which
authority leads multitudes to follow blindly and commit unspeakable
atrocities. The resistance of one man is
a badge of courage.
I believe physicians apply
their power to some extent in every patient encounter. Physicians, wield your
power carefully and always with the aim of benefit to the patient.
May Reduce Risk Of Development Of
PMS.
6-14 CALCIUM
AND VITAMIN D INTAKE AND RISK OF INCIDENT PREMENSTRUAL SYNDROME
Several studies
have suggested that calcium and vitamin D levels are lower in women with PMS,
and that calcium supplementation may prevent the initial development of PMS.
This
case-control study was nested within the large prospective Nurses’ Health
Study. Participants were a subset of women age 27 to 44 (mean = 35). All were
free of PMS at baseline (1991). Cases:
1057 women who developed PMS over a 10-year follow-up. Controls: 1968 women who reported no diagnosis of PMS
and no, or minimal, menstrual symptoms.
Determined dietary
and supplemental intakes of calcium and vitamin D by periodic questionnaires.
Women in the
highest quintile of total vitamin D intake (median of 706 IU) had a relative
risk of new-onset PMS of 0.59 compared with those in the lowest quintile
(median of 112 IU). Benefit was associated with vitamin D from food.
Supplemental vitamin D did not seem to be associated with risk.
Similar benefit
was associated with calcium intake from food.
I abstracted this article because its
conclusions are provocative—certainly not definitive. It raises more
questions: Why did the benefit not
extend to supplements? Is there a reasonable
biological mechanism for the action of calcium and vitamin D? Why no benefit
from whole milk? At a more practical
level—could diet be beneficial in treatment as well as prevention?
I
will watch for more developments.
“These Results Do Not Support Aggressive Treatment Of
Localized, Low-Grade Prostate Cancer.”
This study estimated 20-year survival
of men who were diagnosed with clinically localized PC and treated with
observation or androgen withdrawal therapy. None received prostatectomy for
attempted cure. They were stratified by age at diagnosis and histological
findings. It provides an estimate of the natural progression of PC treated
conservatively.
Fifty eight % of patients received no
treatment; others received androgen suppression (orchiectomy or estrogens).
None received radical prostatectomy for attempted cure.
The median observation period was 24
years.
Men with low-grade PC (Gleason score
2 to 4) had a minimal risk of dying from PC during 20 years. Those with
high-grade PC (Gleason score 7, 8 to 10) had a high probability of dying from
PC within 10 years. Those with scores 5 to 6 had an intermediate risk of dying
from PC.
Cumulative mortality from PC up to 20
years after diagnosis stratified by age and Gleason score (My analysis of Figure p 2099 RTJ):
Men age 55-59 at diagnosis: Died
from PC
Gleason score 2-4 5%
Gleason score 8-10 90% (10% died of other
causes)
Men age 70-74 at diagnosis
Gleason score 2-4 8%
Gleason score 8-10 58% (42% died of other
causes)
The majority of men with high grade
PC die from the cancer regardless of their age at diagnosis. The percentage of
deaths from PC in older men is lower
than in younger men because older men have more competing causes of death. Much
depends on the man’s age at diagnosis.
“Tumor histology still remains the most
powerful predictor of disease progression.” Men with well-differentiated tumors
rarely die of the disease. Men with poorly differentiated tumors frequently die
of the disease within 5 to 10 years despite aggressive interventions including
androgen deprivation. (The study did not include radical prostatectomy.)
Counseling men with Gleason scores of
5, 6, and 7, and a life expectancy of more than 15 years poses the greatest
challenge. Physicians will continue to recommend aggressive treatments in these
patients at the time of diagnosis.
The annual rate of progression of PC
does not increase after 15 years. “These results do not support aggressive
treatment of localized, low-grade prostate cancer.”
None of these patients received PSA screening. At present, the natural
history of PC is influenced by PSA determinations. I wondered . . . What would
have been the natural history if PSA had been available for this study?
A. Many men would have been biopsied. A diagnosis of “cancer’
would have caused great continuing anxiety to the patients and family. Some may
have changed their lifestyles as a result.
B. Many with low-grade Gleason scores would have undergone
radical prostatectomy without benefit, and with risk of serious adverse effects
from surgery.
C. Many men with high-grade scores would have undergone
radical prostatectomy with no chance of cure.
D. Many older men would have undergone radical prostatectomy
without any effect on their life span. They would have died of other causes.
E. Few men would have been cured.
Primary care clinicians should understand the natural history of PC—as
much as it can be presently understood—in order to
advise men regarding PSA screening, and benefits and adverse effects of
surgery.
Screening and surgery should tilt
toward younger men.
“In Absolute Terms The Reduction In Mortality Is Moderate.
Clinical Decision-Making Will Remain Difficult.”
5-9 RADICAL
PROSTATECTOMY VERSUS WATCHFUL WAITING IN EARLY
PROSTATE CANCER
This article reports estimated
10-year results of a trial comparing radical prostatectomy vs watchful waiting (WW)
in patients with early PC.
Cumulative incidence at 10 years: Surgery (%) WW
(%) Absolute difference (%) NNT
Disease-specific mortality 9.6 14.9 5.3 19
Distant metastases 15.2 25.4 10.2 10
Local progression 19.2 44.3 25.1 4
Disease specific survival at 10 y 91% 86%
(Note
that 45% of the surgery group were not cured [10% died; 15% had metastases; 20% local progression]. 15% of the WW group had no evidence of
disease at 10 years.)
“We found that the reduction in
disease-specific mortality as a result of radical prostatectomy was . . . limited to patients younger than 65 years.”
But this observation had limited interpretability because it was based on small
numbers of patients.
“In absolute terms the reduction in mortality is
moderate. Clinical decision-making will remain difficult.”
The slight difference in 10-year disease-specific survival between groups
(5%) impressed me. That 45% of the surgery group was not cured is also
impressive.
All of these patients received PSA screening. The end-result at 10 years
was a very modest (5%) cure rate. The survival rate in the WW group was 85%.
When first introduced, PSA screening was said to be the most important
ontological screen yet developed. Now, the bloom seems to be coming off PSA
screening. The
PSA screening is an important consideration in primary care. Before
screening, all men should receive adequate information about risks as well as
benefits. This applies to older men—especially those with co-morbidity—who
request screening. Screening and surgery should tilt toward younger men.
Primary care clinicians who enthusiastically advise PSA screening assume
a much greater responsibility for the adverse effects that screening may lead
to than when screening is done after persistent requests from the patient.
Still, PSA remains the best screen for PC available today. Many men will
continue to request it. Many primary care clinicians will continue to order it
without much thought.
Undoubtedly, PSA screening, biopsy, and attempts at curative surgery are
grossly over used.
“Is cure necessary when possible?”
Not always. “Is cure possible
when necessary?” Sometimes
Why do we Underuse Treatments That are Beneficial in Trials?
1-2 EXTERNAL
VALIDITY OF RANDOMIZED CONTROLLED TRIALS: To Whom do
the Results of this Trial Apply?
Randomized
controlled trials (RCTs) and
systematic reviews must be internally
validated. (Ie, the design and conduct of RCTs must keep the possibility of
bias to a minimum). To be clinically useful, however, the results must be
relevant to a definable group of patients in a particular clinical
setting. This is termed external validity.
The
most frequent criticism by clinicians of RCTs, systematic reviews, and guidelines
is the lack of external validity. This explains the widespread underuse in
routine practice of treatments that are beneficial in trials and recommended by
guidelines.
Assessment
of external validity requires clinical rather than statistical expertise.
The response to,
and compliance with, treatment can be influenced strongly by the doctor-patient
relationship, placebo effects, and patient preferences. The importance of these factors
outside of trials should not be underestimated. Note the popularity of
“alternative” therapies in which such factors are the
only active ingredients.
The primary care clinician
is a final arbiter of external validity. (Would this application be clinically
useful for Mrs. Jones?)
Beware of surrogate outcomes
in RCTs, of composite outcome measures, underreporting of adverse effects,
and reports by pharmaceutical companies.
Primary
care difficult, challenging, and so rewarding.
Antibiotics Provided Little Advantage Compared With
No-Antibiotics.
6-2 INFORMATION LEAFLET AND ANTIBIOTIC
PRESCRIBING STRATEGIES FOR ACUTE LOWER RESPIRATORY INFECTION
Pharyngitis and acute bronchitis are the main causes of
excess antibiotic prescribing.
This pragmatic
study assessed the effectiveness of 3 different antibiotic strategies for acute
bronchitis.
Randomized,
controlled trial followed over 800 patients presenting to primary care with
acute uncomplicated LRI. Patients with
findings suggestive of pneumonia were excluded—new focal chest signs (focal
crepitations or bronchial breathing); and systemic features (high fever,
vomiting, severe diarrhea). Also excluded patients with
asthma, other chronic or acute lung diseases, cardiovascular disease, or with
previous pneumonia.
Randomized
to: 1) no antibiotic prescribed [control
group], 2) delayed prescription [to be
picked up later], or 3) immediately prescribed antibiotic. The antibiotic of
choice was amoxicillin 250 mg 3 times daily for 10 days, or, if allergic,
erythromycin 250 mg 4 times a day for 10 days.
Compared with no
antibiotics [control group], the other strategies did not significantly alter
cough duration: Delayed prescription shortened duration by 0.75 days; immediate
prescription by 0.11 days. Treatment
group had no effect on duration of other symptoms.
“Compared with
immediate antibiotics, a strategy of either no offer of antibiotics or a
delayed prescription was associated with little difference in duration or severity
of symptoms.” Overall, antibiotics probably do provide modest symptomatic
relief. If a benefit is present, it represents a shortening of only one day in
a relatively long history. “It is
difficult to justify widespread antibiotic prescribing for uncomplicated lower
respiratory infection on this basis, given the dangers of antibiotic
resistance.”
I
was somewhat surprised at the duration of cough symptoms in this group of
patients—a mean total of 3 weeks. However, I believe most patients would experience
a gradual improvement over this period. We are admonished to consider pertussis
in patient with LRI when the cough lasts 3 weeks or more. I presume in
pertussis the cough continues unabated.
I
believe advising patients that antibiotics may be associated with serious
adverse effects (eg, colitis) will do more to tilt them toward accepting only
symptomatic therapy than would advising them of the danger of antibiotic
resistance in the community.
I
have had success in prescribing delayed prescriptions of patients with
uncomplicated lower respiratory infections. The great majority never fills the
prescription. This may be an acceptable means of satisfying a demanding
patient.
In
the
The
decision by primary care clinicians to prescribe or not prescribe, I believe,
will often depend on how “sick” the patient appears.
SENSITIVITY, SPECIFICITY, AND PREDICTIVE
VALUES
6-4 SENSITIVITY, SPECIFICITY, AND PREDICTIVE
VALUES A Review
The authors of the preceding article
calculated the sensitivity, specificity, and predictive values of the waist
circumference test.—the ability of the test to detect insulin resistance and
insulin sensitivity among healthy subjects by using 100 cm as a cut-off point.
I welcome opportunities to review these important statistical measures. I have
done so many times. I still have some difficulty in thinking them through and
calculating them accurately. I used the determinations in the article as an
example.
See the abstract.
Cessation is Difficult to Achieve. When Successful, it Saves
Lives.
2-3 THE EFFECTS OF A
SMOKING CESSATION INTERVENTION ON 14.5-YEAR MORTALITY: A Randomized Trial
The Lung Health
Study entered over 5500 community-dwelling adult volunteers. All were heavy
smokers (mean of 31 cigarettes daily and a history of 40 pack-years). At
baseline, all had modestly impaired FEV1 and FVC, but were asymptomatic. None considered themselves to be ill.
Randomized to:
1) Intervention group received an intensive 10-week smoking cessation program
consisting of a strong physician message and 12
two-hour group sessions using behavior modification and nicotine gum and 2)
Usual care group.
At 5 years, 22%
of the special intervention group had stopped smoking vs 5% of the usual care patients.
Mortality rates
per 1000 person-years at 14 years:
Sustained quitters Intermittent
quitters Continuing smoker
Cardiovascular disease 1.0 1.5 2.9
Lung cancer 1.5 3.0 3.6
The most
prominent difference between groups was observed in the youngest participants.
“It could be argued that smoking cessation was more effective in preventing
truly premature death.”
This
type of intervention would not be feasible in primary care practice.
The
discouraging (yet realistic) outcome of this all-out effort—78% of heavy
smokers failed to achieve cessation even though they received an all-out
intervention, and were aware of a beginning disability from smoking.
This
would tilt efforts to intervene much earlier in life, particularly to prevent
smoking in the first place.
Cessation
benefits all ages. Younger patients can be told their risk of dying at a
relatively young age (35-44) is high as a result of smoking. This might deter a
few.
Statins Reduce C-Reactive
Protein Levels and Improve Outcomes Independently of LDL-Cholesterol
1-13 STATINS FOR ATHEROSCLEROSIS—Autoimmunity,
Inflammation, and C-reactive Protein.
Statin drugs, in addition to inhibiting
synthesis of cholesterol, now appear to directly inhibit inflammation. Two articles in this issue of NEJM confirm
that reducing the inflammatory component of cardiovascular disease with statin
therapy improves clinical outcomes independently of the reduction in
cholesterol. Both studies found that the statin-induced decrease in C-reactive
protein (CRP), a marker of
inflammation, is only weakly correlated with changes in lipid levels.
The
LDL-c lowering effect of statins and their effect on lowering CRP are largely
independent of each other. Patients achieving the lowest CRP levels through
statin therapy had a higher event-free survival at all levels of
LDL-cholesterol.
Only
by assaying both C-reactive protein and cholesterol can the full effect of
statins be identified.
Statins are the “penicillin” of the last of the 20th century
This is not a practical
point at this time. Although it is still “far out”, I included the abstract
because of its potential. We need a more specific agent to reduce C-reactive protein
levels.
CRP is formed in the liver
in response to acute inflammation. It is a non-specific marker.
C(capsule)-reactive protein has an
interesting history. It was first described in 1930 as an indicator of
pneumococcal infection because it reacts with the polysaccharide in the capsule
of the pneumococcus.
“No Indication Of A Net Benefit.”
Current
“Prophylactic
use of a potentially toxic agent can be problematic, particularly in people in
whom comorbidity and polypharmacy are common.” In a prospective observational
study in two large
This
epidemiological modeling study was conducted in a hypothetical population (10
000 men and 10 000 women) selected from a reference population from a state in
Proportional
benefit gained from aspirin in prevention of MI and ischemic stroke vs excess hemorrhage from age 70-74 to
age 100 or to death:
Benefit in preventing Men (n = 10
000) Women (n = 10 000)
Myocardial infarction - 389 - 321
Ischemic stroke - 19 - 35
Harm
Excess GI hemorrhage + 499 + 572
Excess hemorrhagic stroke + 76 + 54
When comparing
net harms vs net benefits of aspirin,
the effects on length and quality of life were equivocal.
“Despite sound
evidence for efficacy, the temptation to blindly implement low-dose aspirin
treatment for the primary prevention
of cardiovascular disease in elderly people must be resisted.” Benefits may be offset by harms.
I
believe low-dose aspirin has an important place in primary prevention of women
at higher risk, and in secondary prevention of cardiovascular disease.
There
is an important clinical downside related to universal prophylactic aspirin
therapy: suppose primary care clinicians
prescribe low-dose aspirin to 1000 women over 10 years. Three or 4 ischemic
strokes might be prevented. But there would be no way of knowing which individuals
of the 1000 benefited. Conversely, a serious hemorrhagic event occurring in 2
of the1000 patients would be self-evident. The clinician might feel
responsible, and the patient and family might blame the clinician for the
disaster.
I
believe primary prevention with aspirin in women at average risk should be
avoided. Obviously, careful clinical judgment based on individual-patient
attributes is required.
“Rapid and Judicious Treatment of Diarrhea, Not Antibiotic
Prophylaxis, Is the Best Recommendation”
5-4 TRAVELERS’ DIARRHEA: HOW TO HIT THE RUNS FOR FIFTY MILLION
TRAVELERS
Prophylaxis and
Treatment of Travelers’ Diarrhea
An article in
this issue of Annals reports a new (to the
The high protection rate of antibiotic
prophylaxis has led to the inescapable conclusion that TD is an infectious
disease. Putative agents appear to be gram negative enteric bacteria sensitive
to many antibiotics. (Doxycycline, trimethoprim-sulfamethoxazole, and
fluoroquinolones are effective. However, unlike rifaximin, they are
absorbed.) These microorganisms are
likely food or water borne. Beware of “dietary mistakes”—fresh unpeeled fruit
and ice.
The editorialist has misgivings about
a preventive policy that would lead to millions of persons receiving
antimicrobial drugs. The most persuasive argument against universal antibiotic
prophylaxis is the existence of excellent treatment alternatives that can
reduce an episode of TD to a few hours of inconvenience. Antimotility drugs
(eg, loperamide—over-the-counter Imodium-AD
each tablet contains 2 mg) act rapidly and are safe. Bismuth subsalicylate (Pepto-Bismol) is also useful for mild disease. For more severe
disease, a fluoroquinolone or azithromycin can be added to the loperamide regimen.
“The current recommendation is to
supply the at-risk traveler with these drugs to be taken as required for
diarrhea, along with the warning to seek medical attention for more severe
symptoms.” “Rapid and judicious treatment of diarrhea, not antibiotic
prophylaxis, is the best recommendation for most travelers.”
Travelers to countries where TD is prevalent should take a packet of
treatment drugs along.
Hope For Reducing The Prevalence Of This World-Wide Scourge.
6-15 BASIC SCIENCE GUIDELINES DESIGN OF NEW TB
VACCINE CANDIDATES
Several
new vaccines which improve immune response are under investigation. They may be
helpful in primary prevention of infection as well as boosting immunity in
those with latent infection.
See the
abstract.
(The entire
Approximately 1% of Crystalline B12 Given Orally
is Absorbed
Vitamin B12 deficiency affects mainly
older people. Symptoms include anemia, neuropathy, and neuropsychiatric
disorders, but deficiency more commonly leads to nonspecific tiredness or
malaise.
In the presence of intrinsic factor,
and normal functioning of stomach, pancreas and terminal ileum, B12 in food can
be absorbed actively with a limited capacity of about 3 ug per meal. The bioavailability of crystalline B12 is
unaffected by the underlying causes of deficiency. Approximately 1% is absorbed
by passive absorption.
Although deficiency is usually treated by
monthly injections of 1000 ug (1 mg), dietary supplements of 1000 to 2000 ug/d
administered orally are as effective in correcting biochemical markers of
deficiency.
“The lowest dose of oral
cyanocobalamin required to normalize mild vitamin B12 deficiency is more than
200 times the recommended daily allowance, which is approximately 3 ug daily.”
The Benefit/Harm-Cost Ratio of Vitamin D May Be Very High
3-8 RECENT DEVELOPMENTS IN VITAMIN D DEFICIENCY
AND MUSCLE WEAKNESS AMONG ELDERLY PEOPLE
Vitamin D
deficiency is common in the elderly (especially in the house-bound and nursing
home patients). Its prevalence is much greater than previously realized. It may
be associated with poor muscle strength, and a tendency to fall, as well as
osteomalacia.
Higher plasma
levels of calcidiol are associated with muscle strength, physical activity, and
ability to climb stairs. Lower levels of calcidiol are associated with falls
among the elderly. A randomized trial reported a 47% reduction in falls and
fractures in elderly women given 800 IU of vitamin D daily (compared with
controls receiving calcium alone) over 12 months.
The author
states that supplementation is often inadequate. 400 IU daily may be
ineffective. In contrast, 800 IU has been shown to significantly reduce the
risk.
Treatment with a
supplement of 800 IU daily should be seriously considered.
It
is important to remember that patients with kidney and liver disease require
special consideration. The kidney is the first step in metabolism of
cholecalciferol to calcidiol. And the liver is involved in the final conversion
to the active hormone, calcitriol.
See
also:
“Effect of vitamin D on
falls” Practical
Pointers April 2004 [4-5]
“Effect of four-monthly
oral vitamin D supplementation on fractures and mortality in man and women
living in the community”
March 2003 [3-4]
“Occult vitamin D
deficiency in postmenopausal
Supplements Containing 800 IU Appear To Reduce Risk Of
Fracture; 400 IU Is Inadequate.
5-3 FRACTURE
PREVENTION WITH VITAMIN D SUPPLEMENTATION
A Meta-analysis of Randomized, Controlled Trials.
This study
estimated the effectiveness of oral vitamin D supplements in preventing hip and
non-vertebral fractures in older persons.
A
dose of 800 IU was associated with a reduction in relative risk of both hip
fracture (RR = 0.74) and non-vertebral fracture (RR = 0.77) compared with
calcium supplements alone or placebo. No significant benefit was observed from
a dose of 400 IU.
The pooled risks indicate the NNT(to benefit one patient) = 45 for hip fracture and 27 for
any non-vertebral fracture.
I believe there will be greater benefit from vitamin D + calcium if they
are started at a younger age. Any benefit in older persons who already are osteoporotic
and have already sustained a fracture would be minimal.
I believe supplemental calcium is required for most Americans. Our diet
is often woefully deficient in calcium.
Benefit/harm-cost ratio is high for both calcium and vitamin D. There is
increasing evidence that the dose should be raised to 800 IU in older persons who live indoors.
Vitamin D given in the usual daily doses is a very safe drug.
May Reduce Risk Of Development Of
PMS.
6-14 CALCIUM AND
VITAMIN D INTAKE AND RISK OF INCIDENT PREMENSTRUAL SYNDROME
Several studies
have suggested that calcium and vitamin D levels are lower in women with PMS,
and that calcium supplementation may prevent the initial development of PMS.
This
case-control study was nested within the large prospective Nurses’ Health
Study. Participants were a subset of women age 27 to 44 (mean = 35). All were free
of PMS at baseline (1991). Cases: 1057
women who developed PMS over a 10-year follow-up. Controls: 1968 women who reported no diagnosis of PMS
and no, or minimal, menstrual symptoms.
Determined dietary and supplemental intakes of calcium and vitamin
D by periodic questionnaires.
Women in the
highest quintile of total vitamin D intake (median of 706 IU) had a relative
risk of new-onset PMS of 0.59 compared with those in the lowest quintile
(median of 112 IU). Benefit was associated with vitamin D from food.
Supplemental vitamin D did not seem to be associated with risk.
Similar benefit
was associated with calcium intake from food.
I abstracted this article because its
conclusions are provocative—certainly not definitive. It raises more
questions: Why did the benefit not
extend to supplements? Is there a reasonable
biological mechanism for the action of calcium and vitamin D? Why no benefit
from whole milk? At a more practical
level—could diet be beneficial in treatment as well as prevention?
I
will watch for more developments.
An increased Risk of Heart Failure Associated with Vitamin E
3-10 IS THERE ANY HOPE FOR VITAMIN E?
Over
the past 3 to 6 years, placebo-controlled trials have consistently shown that
commonly used antioxidant vitamins (E, C, and beta carotene, or a combination)
do not significantly reduce overall cardiovascular
events or cancer.
This editorial
comments on a study which reports a 7-year follow-up of a trial of vitamin E (daily
400 IU of alpha-tocopherol—a natural source). The study was based on a cohort of patients age 50 to 75 who had established cardiovascular
disease or diabetes. There was no statistical benefit from the vitamin in
reducing risk of total cancer or cardiovascular events.
A subgroup
finding reported a possible harmful
effect—an increased risk of heart failure associated with vitamin E.
“In nearly 60
000 studied to date, there was no compelling evidence that higher doses of
vitamin E reduced cardiovascular disease or cancer.”
“Vitamin E supplements
should not be used in patients with vascular disease of diabetes.”
The “antioxidant” theory has become
entrenched in the minds of the public in the
Donepezil May Delay Clinical Progression To
Alzheimer’s Disease
6-10 VITAMIN E AND DONEPEZIL (ARICEPT) FOR THE TREATMENT OF MILD
COGNITIVE IMPAIRMENT
Amnestic (memory loss)
mild cognitive impairment (MCI)
represents a transitional state between the cognitive changes of normal aging
and the earliest clinical features of Alzheimer’s disease (AD). Amnestic MCI refers to
the subtype that has a primary memory component, either alone or in conjunction
with other cognitive-domain impairments, of insufficient severity to constitute
dementia. About 80% of those who meet the criteria for MCI will have AD within
6 years.
MCI is a
transition state between normal aging and dementia (for Alzheimer’s disease in
particular), one in which cognitive deficits are present, but function
preserved. In clinical settings, the term is often used to describe patients
who present with memory loss, but do not have dementia. Even when defined
carefully, MCI is a heterogeneous category that includes some persons with
memory changes of normal aging, some with non-progressive cognitive defects,
some with prodromal AD, and some with prodromal forms of other
neurodegenerative dementias.
This study was
designed to determine if vitamin E or the cholinesterase inhibitor donepezil
could delay the clinical diagnosis of AD in patients with MCI.
Vitamin E had no
effect at any time.
For donepezil .
. . “The observed relative reduction in the risk of progression of 56% at one
year and 36% at two years in the entire cohort is likely to be clinically
significant.”
“Although our
findings do not provide support for a clear recommendation for the use of
donepezil in persons with mild cognitive impairment, they could prompt a
discussion between the clinician and the patient about this possibility.”
Symptoms of
memory loss in older persons should be taken seriously. They may represent the
beginning of AD. This may be an important clinical measure
once more effective treatments become available.
The important
question is . . . What are the cognitive changes of normal aging?
I
believe some degree of memory impairment is almost universal among individuals
over age 80. It usually begins by forgetting names, and recalling them minutes or hours later (“senior moments”). The spectrum
of memory impairment is wide. The definition of amnestic MCI is not settled. At
what point does it predict development of AD? The criteria for diagnosis of
amnestic MCI in the study included patients with difficulties greater than
temporarily forgetting names.
This
study may foretell important developments in drug therapy which may delay the
onset of disabling dementia. The spectrum of forgetfulness of old age is very
broad. When should intervention be considered?
Some elderly patients may well accept
early intervention. A delay of one to two years represents a large proportion
of remaining quality-life. Patients may be willing to accept some adverse
effects of drugs to gain a few years free of dementia of AD. (Note that
anticholinergics do not benefit vascular dementia.)
Others
may wish to wait until adverse effects on daily living become more evident.
I
do not believe memory defects inevitably progress to AD. Keeping mentally and
physically active, continuing a healthy diet, retaining active family and
social connections, and controlling risk factors for cardiovascular disease
will delay or prevent development of dementia in many individuals.
A Circumference Under 100 Cm Rules Out Insulin Resistance And
Hyper-Insulinemia.
6-3 USE OF WAIST CIRCUMFERENCE TO PREDICT INSULIN
RESISTANCE
This study
assessed how effectively different anthropometric markers used in clinical
practice can predict insulin sensitivity. The authors suggest abdominal
circumference is the most powerful independent predictor to rule out insulin
resistance.
Determined height, weight, and waist circumference (midway between
lateral lower ribs and iliac crest). Also determined results from
analyses of plasma for glucose, insulin, and lipid concentrations. Used a
homoeostasis index as a measure of insulin sensitivity [plasma glucose (mol/L) X plasma insulin
(mU/L)/22.5]. A score of 4.0 and greater
was defined as insulin resistance.
Using 100 cm as
a test, the authors determined the sensitivity to diagnose insulin resistance
was between 94-98%; and the specificity was between 61-63%. The positive
predictive values of the test were 61% for men and 42% for women. The negative
predictive value of the test was 98% in men and 97% in women. A waist
circumference under 100 cm was therefore a strong independent predictor in ruling out insulin resistance.
Waist
circumference is a simple tool to exclude
insulin resistance. If the patient has a circumference under
100 cm (40 inches), he or she is very unlikely
to have insulin resistance and hyper-insulinemia. Circumferences above 100 cm
may, or may not, be related to insulin resistance.
I
found this short article provocative. The results require confirmation.
Abdominal girth is an important risk factor for the metabolic syndrome and
cardiovascular disease.
It Has Been Known For Decades That Pertussis Occurs In
Adults. It Is Not A “Zebra” Diagnosis.
5-5 ADULTS
ARE WHOOPING, BUT ARE INTERNISTS LISTENING?
Evidence strongly supports the
inclusion of pertussis in the differential diagnosis of chronic cough illness
(1 month of more) in adults and
adolescents. One
study reported that patients had visited their physicians as often as 9 times
for cough symptoms, and that none of the 153 referrals for cough symptoms
persisting for 2 weeks or longer had pertussis documented as a suspected
diagnosis. Many respondents were not aware that childhood immunization with
pertussis vaccine does not provide lifetime immunity. Many did not know that
the nasopharyngeal swab or aspirate is the preferred method for collection of a
sample for culture. A minority knew that antimicrobial therapy is indicated for
all close contacts of a case-patient.
Clinicians should think of pertussis
when a cough illness exceeds 2 weeks.
“Pertussis is a community-acquired
disease of persons of all ages and deserves greater attention by physicians for
adults.”
Confirmation of diagnosis by culture and PCR is difficult and waiting for
confirmation will delay treatment.
I believe many clinicians will treat
chronic-cough illness empirically with antibiotics.
Potentially A Less Intimidating
Alternative to Warfarin. Concerns about
Hepatotoxicity
2-7 XIMELAGATRAN—Promises and Concerns
Melagatran is a highly-specific direct thrombin inhibitor,
an analogue of hirudin, the thrombin inhibitor found in the medicinal leech. It is a small dipeptide which binds
reversibly to the active site of thrombin. It inhibits clot-bound thrombin as
well as free thrombin. Ximelagatran is a prodrug form of melagatran. It is
rapidly absorbed from the GI tract. When given orally it is rapidly converted to
melagatran. Its antithrombin activity is immediate. Peak blood levels are
attained in 3 hours. It is cleared entirely by renal excretion in 12 hours.
Since
the effect is predictable at a fixed dose, monitoring is not necessary.
This
is not yet a practical point for primary care since the drug is not yet
approved by the FDA. Many attributes of
the drug make it a very attractive anticoagulant: immediate action when given orally; a fixed dose
without need for monitoring; rapid renal clearance; no food or drug interactions; active against clot-bound as well as free
thrombin; reversible binding to
thrombin.
If
the risk of hepatotoxicity can be controlled by monitoring, I believe it will
be a major therapeutic advance.