MEDICAL SUBJECT HEADINGS
HIGHLIGHTS-INDEX
EDITORIAL COMMENTS
Statement
from the Editor/publisher
This
index is intended to be a reference document.
Each medical subject heading is linked to one or more “Highlights and Editorial Comments” of articles abstracted during the last half of
2004. It 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, [10-12] indicates the 12th abstract
published in the October issue.
Each
monthly issue for the past 5 years can be found on the website
(www.practicalpointers.org). This makes 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.
HOW THE ARTICLES ABSTRACTED JULY-DECEMBER 2004 INFLUENCED MY PRACTICE
MEDICAL
HEADING SUBJECTS (MeSH) JULY-DECEMBER 2004
AYURVEDIC HERBAL MEDICINE
PRODUCTS
BARIATRIC SURGERY (See OBESITY)
CALCULATING THE RISK OF
DISEASE
CANCER (See also BREAST CANCER, PROSTATE CANCER)
CANCER OF THE CERVIX (See HUMAN PAPILLOMA VIRUS)
CHOLESTEROL (See STATIN DRUGS)
FATTY LIVER DISEASE (See HEPATOBILIARY
DISEASE)
FEEDING TUBE (See DEMENTIA)
GLYCEMIC
INDEX; GLYCEMIC LOAD (See also DIABETES)
HEMOGLOBIN A1C (HbA1C; See DIABETES)
HEPATOBILIARY DISEASE (See DIABETES)
HORMONE REPLACEMENT THERAPY (See MENOPAUSE)
MEDITERRANEAN DIET (See DIET)
MICROALBUMINURIA (See DIABETES)
MIGRAINE
(See HEADACHE)
MULTIPLE CONDITIONS;
MULTIPLE MEDICATIONS
NON-ALCOHOLIC FATTY LIVER DISEASE (See DIABETES [12-3]
NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (See
COX2 INHIBITORS)
POSTCHALLENGE PLASMA GLUCOSE (See DIABETES)
POSTMENOPAUSAL
HORMONE THERAPY
PROSTATE SPECIFIC ANTIGEN (See PROSTATE CANCER [7-4] [7-5] [11-5])
SHARED MEDICAL DECISION
MAKING
VITAMINS (See ANTIOXIDANTS)
HIGHLIGHTS AND EDITORIAL COMMENTS JULY TO DECEMBER 2004
ALDOSTERONE
7-10 SERUM ALDOSTERONE AND THE INCIDENCE OF
HYPERTENSION IN NON-HYPERTENSIVE PATIENTS
“All known monogenic forms of hypertension in humans can
be traced to defects in renal sodium handling.”
The potential role of aldosterone in the pathogenesis
of essential hypertension is of great interest. No studies have prospectively
evaluated the effect of serum aldosterone on the incidence of hypertension.
Do
aldosterone levels within the physiological
range influence the risk of hypertension?
Higher aldosterone levels within the normal physiologic range predispose to hypertension. For
each quartile increment of serum aldosterone there was a 16% increase in the
risk of an increase of an elevation of BP category, and a 17% increase in risk
of developing hypertension.
Relative to the lowest quartile of aldosterone, the
highest quartile was associated with a 1.6-fold risk of an elevation in BP
category and a 1.6-fold risk of developing hypertension. There was a linear
increase with each quartile.
“Increasing aldosterone levels within the physiologic
range may predispose to hypertension through promotion of sodium retention,
potentiation of action of angiotensin II, and impairment of endothelial
function.”
I abstracted
this article as a matter of interest. It has no practical importance at this
time. Watch for follow-up studies. Are we beginning to take “essential” out of
essential hypertension? RTJ
10-8 ANTIOXIDANT SUPPLEMENTS OF PREVENTION OF
GASTROINTESTINAL CANCERS
“Oxidative
stress can cause cancer.” The GI tract is thought to be the major site of
antioxidant action. Many observational epidemiological studies have reported
that high intakes of fruit and vegetables (rich in antioxidants) are associated
with a lower incidence of cancer. Results of randomized trials of one or more
selected antioxidant supplements have been contradictory.
This review identified 14 randomized trials (n = 170
000 subjects) comparing antioxidants vs
placebo for
prevention of GI cancers. The quality of the trials
was generally high.
The meta-analysis did not show any significant benefits of supplementation with
beta-carotene, vitamins A, C, and E (alone or in combination) vs placebo for esophageal, gastric,
colorectal, pancreatic and liver cancer.
An analysis
of 7 high-quality trials showed that antioxidants were associated with a significantly
increased mortality. “Our result for the detrimental effect of
antioxidant supplements on mortality was unexpected.”
Four trials
(only one was high quality) reported that selenium showed significant benefit on incidence of GI cancers.
“Our systematic review contains several major
findings.” Beta-carotene, vitamin A, and vitamin E supplements given alone or
in combination do not seem to have much effect on the prevention of
gastrointestinal cancers. Further, they seem to increase overall mortality. However, 95% confidence intervals were
large in the analysis of single cancer types and could be compatible with
either beneficial or harmful effects.
Most trials have investigated the effects of antioxidant
vitamins given at substantially higher doses than those usually found in a
balanced diet, and some trials used dosages well above the recommended upper
intake levels. This might be a cause for the absence of the expected protective
effect, and for the increase in mortality associated with high-dose antioxidant
supplements.
The results should not be translated to the potential
effects of vegetables and fruits, which are rich in antioxidants. Many
substances they contain have been postulated to have anticarcinogenic
properties. Data on the effect of fruits and vegetables on cancer have been
conflicting.
Randomized
trials set up to study prevention of lung cancer showed that beta-carotene
actually increased the risk of
disease. A trial of patients at high-risk of cardiovascular disease showed no benefit after 5 years treatment with
a supplement combination. “Antioxidant supplements are not having a good
press.”
The study
found no evidence of benefit (or harm) in the combined group of 5 cancers. However,
there were 2 important exceptions: vitamin C and selenium. There was almost no
data for vitamin C used alone in cancer prevention. For selenium there was
evidence of cancer protection, although on further analysis the benefit was
confined to liver cancer.
“The
prospect that vitamin pills may not only do no good, but also may kill their
consumers is a scary speculation given the vast quantities that are used in
certain communities.” However, these results must be considered preliminary.
Nutrient
deficiency may increase risk of disease. Replacement in deficient states may
confer benefits. But for nutritionally replete individuals, excess intake may
harm.
A randomized, placebo-controlled 7-year
trial from France (Archives Int. Med. November 22, 2004) presented evidence that low-dose antioxidant
supplements reduced total cancer incidence and all-cause mortality in men but
not in women. The issue is not yet
settled. We can advise patients that as
of this date no benefit from high-dose individual vitamins has been
demonstrated for cancer prevention.
I would discourage use of high-dose
individual vitamins. I would encourage use of supplements not exceeding the
recommended daily dose.
11-4 THE SU.VI.MAX STUDY: Trial of Health
Effects of Supplementary Antioxidants.
This study tested the efficacy of nutritional doses of supplements
containing a mixture of antioxidant vitamins and minerals in reducing incidence
of cancer, CVD, and all-cause mortality in a general population.
Subjects were randomized to: 1) vitamin-mineral supplement, or 2) placebo
daily
The daily supplement contained:
Ascorbic acid 120
mg
Vitamin E 30
mg
Beta-carotene 6
mg
Selenium 100
ug
Zinc 20
mg
There was a statistically significant
protective effect in men, but not in women:
Cancer incidence in men:
Intervention 3.5%;
Placebo 4.9%. Absolute difference = 1.4% NNT 7 years = 71
Total mortality in men
Intervention 1.6%;
Placebo 2.5% Absolute difference = 0.9% NNT 7 years = 111
The authors speculate that the difference
in outcomes of men vs women might be
due to a generally lower intake and plasma concentration of antioxidants (especially
beta-carotene) in men. Indeed, baseline serum concentrations were lower in men.
The study reinforces the general recommendation of a
life-long diversified diet containing an abundance of foods rich in
antioxidants.
Is the
putative benefit of supplements clinically important? I believe it is.
How can we
apply this information to primary care in the USA?
I believe at
this time we should advise against high doses of individual vitamins and
minerals. There is no evidence of benefit and there is evidence of possible
harm.
I believe it
is likely that any benefit from supplements will be in individuals whose
nutritional status is borderline. In primary care practice, we cannot assess
the nutritional status of every individual patient.
I believe therefore that a routine recommendation for
a daily low-dose supplement for adults is reasonable. Although in adequately
nourished individuals this may not bring any benefits in protecting against
cancer or cardiovascular disese, the supplements do contain, as an added
attraction, vitamin D and folic acid which may bring benefits.
10-4 ASPARTAME AND ITS EFFECTS ON HEALTH
Aspartame (NeutraSweet; Equal; Generic) consists of
two amino acids—phenylalanine and aspartic acid. Both are contained in normal
dietary proteins. Aspartame is 200 times sweeter than sucrose. The European
population consumes about 2000 tons annually as a substitute for sugar.
Is it
harmful? The European Scientific
Committee on Food was convinced in 1988 that aspartame was safe. The committee conducted a further review
encompassing over 500 reports in 2002.
It concluded from biochemical, clinical, and behavioral research that a
daily intake of up to 40 mg/kg/day remained entirely safe—except for people
with phenyketonuria. Does aspartame
embody a healthy way of life and reduce prevalence of obesity? In most Western
countries, sugar provides about 10% of total calories (50 g daily, or about 200
kcal). If this were entirely replaced by a non-nutritive, non-caloric sweetner,
“obesity could indeed be vanquished - assuming these calories were not
replaced”. However, evidence that
aspartame prevents weight gain or obesity is generally inconclusive.
One packet of generic aspartame contains 35 mg.
An “acceptable daily intake” = up to 3500 mg, or 100 packets, much less than
usually consumed. (Persons who drink many sweetened soft drinks daily may
approach this quantity.)
One
rounded teaspoon of sucrose (5 g) contains 20 kcal. If I added a teaspoonful of
sugar to each of my 3 cups of coffee daily in place of 3 packets of aspartime
(and all other intake remained constant) my caloric intake would increase by 60
kcal each day. By my calculation, if I added this amount to my daily caloric
intake, and assuming perfect metabolism and conversion into fat tissue, I would
gain over 5 pounds a year.
I
believe sweeteners are a reasonable ingredient in the diet of persons who tend
to be overweight and obese, and especially in persons with diabetes. Primary
care clinicians should so advise them.
Use in place of sucrose will reduce postprandial blood glucose levels
and reduce a risk factor for cardiovascular disease.
12-5 ASPIRIN USE AMONG PATIENTS WITH DIABETES
Adults with diabetes, but with no clinical cardiovascular disease, may have risk of CVD events
similar to non-diabetic adults with
established CVD.
Strategies to prevent CVD events in persons with
diabetes are underused. Aspirin effectively reduces risk of first and
subsequent myocardial infarction in patients with diabetes as well as in those
without. Many adults with diabetes do not use it.
This study assessed regular aspirin use among adults
with diabetes between 1997 and 2001.
Use remained less than ideal for patients with CVD.
One quarter of diabetic patients with established heart disease or stroke did
not use aspirin. Among those with risk factors
for CVD (hypertension, dyslipidemia, smoking) 60% did not use aspirin. Almost
2/3 of those without CVD did not use aspirin.
Overall use by women was lower than by men.
Although aspirin use in patients with diabetes is
increasing, use is suboptimal, especially in women, younger patients, and in
those with major CVD risk factors.
The
benefit/harm-cost ratio of aspirin is among the highest of any drug.
Should all
patients with diabetes take aspirin? I
believe in the great majority the benefits outweigh risks. Risks of aspirin in
younger persons with no other risk factors for CVD may outweigh benefits. But
even in younger persons the duration of diabetes should be considered.
I believe at
times primary care clinicians simply forget to recommend aspirin.
7-6 PHARMACOLOGICAL MANAGEMENT TO REDUCE
EXACERBATIONS IN ADULTS WITH ASTHMA
Exacerbations are one of the most important endpoints
for clinical trials of asthma. They represent the period of greatest risk of
emergency visits, hospitalization, and death.
Corticosteroids are potent (but nonspecific)
anti-inflammatory agents. Inhaled corticosteroids (ICS) are the single most effective therapy for adult patients with
asthma who require more than an occasional inhalation of a short-acting beta
agonist. Low doses are first-line
therapy. Since airway inflammation is present even in mild disease, inhaled
corticosteroids are first-line treatments of patients who need more than an occasional
inhalation of short-acting beta agonists. Higher doses (with or without an
added long-acting beta-agonist) can be added. With long-term therapy, risk of
adverse effects increases. Proper inhaler technique, use of a spacer, and mouth
rinsing after each actuation significantly reduce systemic absorption. Patients
should be so educated.
By themselves, long-acting inhaled beta agonists have
only a modest beneficial effect in reducing exacerbations. When added to
inhaled corticosteroids, they do help to reduce exacerbations. Monotherapy is
best avoided. It its less effective than ICS.
Lifestyle management leads to the use of a minimal
amount of medication: smoking cessation, eliminating allergens, weight loss if
overweight or obese (this has been demonstrated to reduce symptoms and improve
lung function and quality-of-life in patients with asthma). If smoking
continues, oral corticosteroids do not lead to significant improvement.
Oral corticosteroids, leukotriene modifiers, and theophylline can occasionally be used
as add-on therapy.
The treatment
table on page 373 is helpful.
Smokers
should be told—“You will not get better unless you stop smoking.”
AYURVEDIC HERBAL MEDICINE PRODUCTS
12-7 HEAVY METAL CONTENT OF AYURVEDIC HERBAL
MEDICINE PRODUCTS
Ayurvedic medicine originated in India more than 2000
years ago. It relies heavily on herbal
medicine products (HMP). HMPs are
marketed as dietary supplements under the Dietary
Supplement Health and Education Act. Proof of safety and efficacy is not
required.
Ayurvedic HMPs containing heavy metals are readily
available in the USA. This study determined the prevalence and concentrations
of heavy metals in Ayurvedic HMPs.
Fourteen of 70 (20%) HMPs tested contained heavy
metals:
No. containing Median
concentration—mg/gram Range
mg/gram
Lead 13 0.040 0.005 to 37
Mercury 6 20 0.03 to 104
Arsenic 6 0.4 0.037 to 8
Taken as recommended by the manufacturer, heavy metal
intoxication may result. One in 5 Ayurvedic HMPs produced in South Asia
contains potentially harmful levels of lead, mercury, and/or arsenic. Users are
at risk.
Traditional medicines from China, Malaysia, Mexico,
Africa, and the Middle East have also been shown to contain heavy metals.
The recent
furor over unreported adverse effects of Merck’s Vioxx led me to include this
study. Can you imagine the furor which would occur if a product of Merck was
reported to contain arsenic, mercury, or lead?
Our drug oversight system is schizophrenic.
The term
Ayur-veda comes from the Sanskrit meaning Life (health) and knowledge. Google
presents over 1 million citations. The wide range of products available, which
are said to be all “natural”, include nostrums for vitality and strength;
healthy blood and skin; healthy hair growth; proper function of the immune
system, heart, joints, muscles, kidneys, adrenal, liver, lung, and reproductive
system; mental clarity; control of blood glucose; and depression.
Mammographic screening of women between ages 50-70 can
reduce mortality from BC by about 25%. The consensus is that BC screening in
this age group is effective. Although screening is frequently offered to women
under age 50 who have a genetic predisposition, efficacy is unproven.
Preliminary results of screening studies with mammography reported a low
sensitivity for detecting BC in these women.
This study compared the efficacy of magnetic resonance
imaging (MRI) with that of
mammography for screening this group of younger, high-risk women (mean age 40).
MRI detected
32 of 45 BCs (22 of these were not visible on mammography). Missed 13 of 45
(including 5 of 6 DCIS, 4 interval cancers, and 1 detected by clinical
examination.)
Mammography detected
18 of 45 BCs (10 of which were visible on MRI)’ missed 27 (including 22 visible
on MRI), but detected more DCIS (5 of 6)
With
respect to all BCs: Sensitivity Specificity
Clinical examination 18% 98%
Mammography 40% 95%
MRI 71% 90%
In younger women at high risk for BC due to a genetic
predisposition or a strong family history.
MRI
detected more BCs than mammography ( 71%.vs 40% ). The specificity of MRI was lower
(more false positives—10% vs 5%).
MRI detected 20 cancers that were not detected by
mammography or clinical examination. Tumors tended to be smaller and positive
nodes were present in only one case.
Comment:
As usual, a
test with a high sensitivity (high % of true positive tests) is associated with
a lower specificity (high % of false
positives). In this group, MRI detected
many more BCs than mammography, but the higher false positive rate led to more
follow-up examinations and biopsies. Women age 40 have more dense breast
tissue. This makes interpretation of mammography more difficult.
I wonder if
this study might reduce the frequency of prophylactic mastectomy in high risk
women. RTJ
7-3 BREAST CANCER SCREENING WITH MRI: What Are The Data For Patients At High Risk?
The average lifetime risk of BC in American women is
one in seven. This risk increases in women with a strong family history of BC,
and an inherited mutation (BRCA genes) Women with BRCA mutations make up about
5% to 10% of women with BC. Their risk of ovarian cancer is also high.
Cumulative risk of BC of women with these mutations
range from 3% at age 30, to 50% by age 50, and to 85% at age 70. These BCs
often occur at a younger age, have “pushing margins”, a high nuclear grade, and
lack estrogen receptors. Cancers in these women grow rapidly.
MRI is highly sensitive in detecting BC. Disadvantages
include cost, variations in technique and interpretation, imperfect
specificity, and variations in enhancement during the menstrual cycle (midcycle
is optimal). MRI screening will likely be refined and standardized. “Whether
the excellent results reported can be achieved in primary care practice remains
to be determined.”
Discovering
and removing a BC in these high-risk women does not end surveillance. Screening
the remaining breast tissue must continue after surgery. Considering the
lifetime need of frequent screening and the continuous anxiety associated, I
can understand that many women would grow weary and opt for bilateral
prophylactic mastectomy RTJ
CALCULATING THE RISK OF DISEASE
7-9 CALCULATING THE RISK OF DISEASE www.yourdiseaserisk.harvard.edu
A review note in BMJ July 24, 2004; 329: 237 calls
attention to an online tool for determining an individual’s risk for five of
the most important disease groups in the USA (cancer, diabetes, heart disease,
stroke, and osteoporosis). It is
presented by The Harvard Center for Cancer Prevention, part of the Harvard
School of Public Health. It is an expanded version of the center’s cancer risk
assessment website.
The site is an interactive educational tool that seeks
to encourage healthy lifestyles. It questions the inquirer’s eating habits,
drinking, and exercise, and offers personalized tips for disease prevention.
I accessed
this site on August 13, 2004 and completed the heart disease risk evaluation.
Individuals can easily and quickly complete the 21 or more questions asked. It
includes all components of the Framingham Risk Score except HDL-cholesterol.
In addition
it asks for past history of heart disease, family history, waist size,
diabetes, 7 different questions about diet and alcohol, vitamin supplements,
and exercise.
On completion
it presents a colored risk scale (low to high) and places the individual’s
estimated risk compared with average.
A useful
addition is a list of tips on how you can reduce your individual risk. I
received 5 different tips to reduce my risk. RTJ
10-8 ANTIOXIDANT SUPPLEMENTS OF PREVENTION OF
GASTROINTESTINAL CANCERS
“Oxidative stress can cause cancer.” The GI tract is thought to be the major site of antioxidant action. Many observational epidemiological studies have reported that high intakes of fruit and vegetables (rich in antioxidants) are associated with a lower incidence of cancer. Results of randomized trials of one or more selected antioxidant supplements have been contradictory.
This review identified 14 randomized trials (n = 170 000 subjects)
comparing antioxidants vs placebo for
prevention of GI cancers. The quality of the trials was generally high.
The
meta-analysis did not show any
significant benefits of supplementation with beta-carotene, vitamins A, C, and
E (alone or in combination) vs
placebo for esophageal, gastric, colorectal, pancreatic and liver cancer.
An analysis
of 7 high-quality trials showed that antioxidants were associated with a
significantly increased mortality.
“Our result for the detrimental effect of antioxidant supplements on mortality
was unexpected.”
Four trials
(only one was high quality) reported that selenium showed significant benefit on incidence of GI cancers.
“Our systematic review contains several major findings.” Beta-carotene,
vitamin A, and vitamin E supplements given alone or in combination do not seem
to have much effect on the prevention of gastrointestinal cancers. Further,
they seem to increase overall
mortality. However, 95% confidence intervals were large in the analysis of
single cancer types and could be compatible with either beneficial or harmful
effects.
Most trials have investigated the effects of antioxidant vitamins given
at substantially higher doses than those usually found in a balanced diet, and
some trials used dosages well above the recommended upper intake levels. This
might be a cause for the absence of the expected protective effect, and for the
increase in mortality associated with high-dose antioxidant supplements.
The results should not be translated to the potential effects of
vegetables and fruits, which are rich in antioxidants. Many substances they
contain have been postulated to have anticarcinogenic properties. Data on the
effect of fruits and vegetables on cancer have been conflicting.
Randomized
trials set up to study prevention of lung cancer showed that beta-carotene
actually increased the risk of
disease. A trial of patients at high-risk of cardiovascular disease showed no benefit after 5 years treatment with
a supplement combination. “Antioxidant supplements are not having a good
press.”
The study
found no evidence of benefit (or harm) in the combined group of 5 cancers.
However, there were 2 important exceptions: vitamin C and selenium. There was
almost no data for vitamin C used alone in cancer prevention. For selenium
there was evidence of cancer protection, although on further analysis the
benefit was confined to liver cancer.
“The
prospect that vitamin pills may not only do no good, but also may kill their
consumers is a scary speculation given the vast quantities that are used in
certain communities.” However, these results must be considered preliminary.
Nutrient
deficiency may increase risk of disease. Replacement in deficient states may
confer benefits. But for nutritionally replete individuals, excess intake may
harm.
A
randomized, placebo-controlled 7-year trial from France (Archives Int. Med. November
22, 2004) presented evidence that low-dose antioxidant supplements reduced
total cancer incidence and all-cause mortality in men but not in women. The issue is not yet settled. We can advise patients that as of this date
no benefit from high-dose individual vitamins has been demonstrated for cancer
prevention.
I
would discourage use of high-dose individual vitamins. I would encourage use of
supplements not exceeding the recommended daily dose.
ABCS
OF CARDIOVASCULAR DISEASE RISK MANAGEMENT
A B C
Aspirin
Beta blocker Cholesterol management
ACE
inhibitor BP control Cigarettes
D E
Diet
and weight Exercise
Diabetes
Ejection
fraction.
I believe
checklists are of value to primary care clinicians. Many effective preventive
measures are not prescribed when they are indicated.
Most of these
applications are also applicable to primary prevention.
I believe
aspirin, beta-blockers, ACE inhibitors, statins, and antihypertension drugs are
essential components of the list. Full doses may not be needed. Administration
can go low and slow. A pill cutter can drastically reduce cost.
Life-style
changes mandatory.
My wife and I
have found checklists helpful when we go on trips. We have a list of things to
do to set the apartment straight before leaving, and a list of things we should
not forget to take along. Almost every time, on going through the lists, we
note one or two items we have forgotten.
Clinical
practice has become so complex, primary care needs more check lists, RTJ
8-6 PRIMARY PREVENTION OF CARDIOVASCULAR
DISEASE WITH ATORVASTATIN IN
Current prescription rates for lipid lowering drugs in
patients with DM2 remain low, even in patients with established cardiovascular
disease (CVD).
This study assessed the effectiveness of a 10 mg dose
of atorvastatin (Lipitor) vs placebo in primary prevention of CVD in patients with DM2. None had high
concentrations of LDL-c. The trial was stopped 2 years early because of
demonstration of significant benefit.
None had documented history of CVD. All had at least
one risk factor: retinopathy, macro- or
micro-albuminuria, current smoking, or hypertension. The risk of a major
cardiovascular event in these patients was 10% over 4 years.
Incidence of major cardiovascular events was 25 per
1000 person-years at risk in the placebo group vs 15 per 1000 person-years at
risk in the atorvastatin group. Therefore, allocation of 1000 patients to
atorvastatin would avoid 37 first major events over a 4-year follow-up. 27
patients would need to be treated for 4 years to prevent one event. [NNT (for
4 years to benefit one) = 27]
“The debate about whether all patients with DM2 warrant statin therapy should now focus on
whether any patients can reliably be identified as being at sufficiently low
risk for this safe and effective treatment to be withheld.”
These data challenge the use of a particular threshold
level of LDL-c as the sole arbiter of which patients with DM2 should receive
statin therapy (as in the case of most current guidelines). Target levels of
LDL-c (100 mg/dL) could be lowered.
An editorialist comments: The conclusions of the study—“Seems too far-fetched in view of
the available clinical trials and epidemiological data”. He cites 4 large
studies of lipid control which contained many patients with DM2. Two of the
four did not report a statistically significant reduction in coronary disease.
Two did.
Clinical trials enroll carefully selected patients.
The results cannot necessarily be extrapolated to primary care practice. Many
patients may be at low risk and the benefit/ harm-cost ratio may be too low to
warrant long-term treatment. Some may be at higher risk of adverse effects from
statins. As always, individualization is required.
I believe the
majority of patients with DM2 will benefit from statin therapy for primary
prevention. Most will have one or more additional
risk factors. There would be no question regarding secondary prevention.
Authors and
publishers persist in presenting relative benefits (rather than absolute
differences). Thus, they reiterate that treatment with atorvastatin was related
to a 37% reduction in major coronary events; a 31% reduction in coronary
revascularizations; a 48% reduction in stroke; and a 27% reduction in deaths.
This can be
very misleading. I believe statements of relative benefits should be eliminated
from published reports.
9-3 ASSOCIATION OF HEMOGLOBIN A1C WITH
CARDIOVASCULAR DISEASE AND MORTALITY IN ADULTS
Diabetes raises the risk of macro-vascular disease as well as micro-vascular disease. Evidence suggests that the relation between
plasma glucose and macro-disease (cardiovascular disease; CVD) is continuous and does not have obvious thresholds.
In this study of over 10 000 subjects, the risk of
CVD, CHD and mortality increased continuously as HbA1c rose. Cardiovascular
disease events increased continuously from 6.7 per 100 men with HbA1c less than
5% to 35 per 100 men with HbA1c over 7%. The risk for CHD was significantly
increased in those with HbA1c 5.0% to 5.4% compared with those with HbA1c
concentrations less than 5%. This
included individuals without
diabetes.
Each increase of HbA1c of 1% was associated with a
relative risk of 1.26 for death from any cause. The relationship was apparent in persons without known diabetes.
(Only 193 subjects had known diabetes.)
HbA1c levels were significantly associated with
all-cause mortality and coronary and cardiovascular disease even below the
threshold commonly accepted for the diagnosis of diabetes. Each increase of
HbA1c of 1% was associated with a 20% to 30% increase in mortality and
cardiovascular events. The gradient was apparent through the population range
from less than 5% up to 6.9%.
Subjects with HbA1c over 7% made up 4% of the sample
and contributed about 25% of the excess mortality.
Reduction in HbA1c levels in persons without diabetes may lessen their risk.
The
metabolism of glucose is related to risk of cardiovascular disease. A healthful
lifestyle should include attempts to control postprandial glucose levels in
patients without diabetes as well as those with diabetes. Diets containing a low glycemic load are an
important part of healthy living. RTJ
9-4 GLYCOSYLATED HEMOGLOBIN: FINALLY READY FOR
PRIME TIME AS A CARDIOVASCULAR RISK FACTOR.
The societal burden of the diabetic epidemic is being
fueled by our current lifestyle. Diabetes is just the measured tip of a much
larger “dysglycemic iceberg”.
It is now clear that fasting and 2-h PG levels well
below the diabetes cutoffs are cardiovascular risk factors. And that a
progressive relationship between PG and CVD risks extends from normal glucose
levels right into the diabetic range, with no clear lower threshold.
Evidence is accumulating that HbA1c is a progressive
risk factor for CVD in people without
diabetes as well as people with diabetes. A HbA1c level of 6.59% in a non-diabetic person predicts a higher
CVD risk than a HbA1c of 5.5%. Even after excluding individuals with a HbA1c
level of 7% and greater, with diabetes, and with a history of heart disease,
the increase in risk for CHD, CVD, and total mortality for every 1% rise in
HbA1c was 40%, 16%, and 26% respectfully.
We can conclude that HbA1c is an independent and
progressive risk factor for incident CVD regardless of diabetes status.
“Glycosylated hemoglobin level can now be added to the list of other clearly
established indicators of CVD risk.” “The presence or absence of diabetes is
likely to become less important than the level of glycosylated hemoglobin in
the assessment of CVD risk. Reducing HbA1c in both diabetic and non-diabetic
persons may reduce cardiovascular risk.”
It will be
interesting to find out the relative risks of HbA1c and hyperinsulinemia
compared with lipids. Could it be that markers of a stressed glucose-insulin
metabolism will become clinical risk indicators as important as LDL-c and
HDL-c? This would include the 2-hour
postprandial glucose as well as the HbA1c level. Could food sugars become as
important a risk factor as saturated fats? Excess sugar intake is related to
obesity and the metabolic syndrome, and in turn to hypertension,
hyperinsulinemia, and dyslipidemia.
I believe, at
the present stage of our knowledge, we should consider aberrant glucose
metabolism an important risk factor for CVD and act on it. RTJ
10-6 COXIBS AND CARDIOVASCULAR DISEASE
Recently Vioxx (a selective COX-2 inhibitor) was
removed from the market by Merck following the results of a trial designed to
test effects on adenomatous polyp formation in the colon. The data and safety
monitoring board took action to stop the study prematurely because of a
significantly increased incidence of serious thromboembolic adverse events (vs placebo) in the group receiving 25 mg
of Vioxx daily. The incidence of
myocardial infarction and thrombotic stroke in the two groups began to diverge
after a year. FDA had approved the 3 COX-2 inhibitors on the basis of trials
that typically lasted three to six months.
In the colon polyp study, which enrolled patients
without known cardiovascular disease, 3.5% of those receiving Vioxx and 1.9% of those receiving
placebo had a myocardial infarction or stroke. (Absolute difference = 1.6%; NNT to harm one patient = 63.) This amounts to an excess of 16 extra events
per 1000 treated. And this was in a group with presumably low risk.
Considering
the tens of millions of patients who were taking rofecoxib…“We are dealing with
an enormous public health issue.” “Even a fraction of a percentage excess in
the rate of serious cardiovascular events would translate into thousands of
affected persons.”
COX-2 inhibitors blunt the production of prostaglandin
I2
(a factor which protects endothelium). They do not blunt the production of
thromboxane (a risk factor for thrombosis). A single mechanism of COX-2
inhibitors (depressing I2 while leaving thromboxane intact) might elevate BP,
accelerate atherogenesis, and predispose to thrombosis. The higher the patient’s intrinsic risk of
cardiovascular disease, the more likely the manifestation of a clinically
important adverse event.
“We now
have clear evidence of an increase in cardiovascular risk that revealed itself
in a manner consistent with a mechanistic explanation that extends to all coxibs.”
How should
clinicians respond? Selective
inhibitors of COX-2 remain a rational choice for patients at low cardiovascular
risk who have had serious gastrointestinal events, especially while taking
traditional NSAIDs. “It would appear
prudent to avoid coxibs in patients who have cardiovascular disease, or who are
at risk for it.”
This
is discouraging. Primary care clinicians are often admonished not to prescribe
a new drug until it has been in general use for 2 or 3 years (unless it has
unique benefits). Two or 3 years of general use would presumably reveal any
adverse effects not demonstrated in trials. Now we find that, after 5 or more
years of general use, Vioxx has unreported and serious adverse effects. I
suspect that more established drugs will be discovered to have unsuspected
long-term serious adverse effects. This reinforces the old adage that “The best
medicine is no medicine”.
It
has long been realized that NSAIDs increase risk of hypertension and heart
failure. It appears that the risk is
augmented in patients taking COX-2 inhibitors.
The
FDA and the drug companies manufacturing other COX-2 inhibitors now must
conduct trials to determine cardiovascular risk of their products as compared
with placebo. Meanwhile, primary care clinicians should be cautious about
prescribing any coxib.
10-5 COMPARATIVE ANALYSIS OF INDIVIDUALS WITH
AND WITHOUT CHIROPRACTIC COVERAGE.
There is
evidence supporting the efficacy of chiropractic care for back pain. A
comprehensive review reported that spinal manipulation was better, and no
trials found it significantly worse, than conventional treatment.
This
retrospective study analyzed claims data covering a 4 year period. It compared
more than 700 000 health plan members who had additional chiropractic coverage vs over 1 million members without
coverage.
Compared
with those without coverage, members with chiropractic coverage had lower annual costs (by $200). They also
had a lower average back-pain
episode-related cost.
Having
coverage was associated with a 1.6% decrease in total annual health care costs.
Back pain patients
with chiropractic coverage had lower utilization of plain radiographs and MRI;
fewer hospitalizations; less surgery and inpatient care.
Chiropractic
care sought by members with insurance coverage was more often substituted for
usual medical care. It was less often an add-on care.
Patients
treated for back pain by chiropractors tend to be more satisfied than those
treated by MDs.
The study
raises the intriguing possibility that chiropractic may in fact be the more
economic approach to the management of the complex, ill-defined, recurrent, and
often refractory symptoms of back pain.
My primary advice for a patient consulting
me for back pain would be to keep on being as active as possible. Stay out of
bed. Take acetaminophen or an NSAID temporarily. In most cases the pain will
abate spontaneously. For more protracted back pain, I would not hesitate to
refer to a chiropractor well established in the community with whom I was
personally acquainted. I would not refer for conditions other than back pain.
9-8 PHYSICAL ACTIVITY, INCLUDING WALKING, AND
COGNITIVE FUNCTION IN OLDER WOMEN
This study examined the relation of long-term regular
physical activity, including walking, to cognitive function in a large cohort
of women. Higher levels of activity were associated with better cognitive
performance. On a global score combining results of all cognitive tests, women
in the second through the fifth quintile of energy expenditures scored an
average of 0.06, 0.06, 0.09, and 0.1 standard units higher than women in the
lowest quintile.
Compared with women in the lowest physical activity
quintile, those in the highest quintile had a 20% lower risk of cognitive impairment.
“In this large prospective study of older women,
higher levels of long-term regular physical activity were strongly associated
with higher levels of cognitive function and less cognitive decline. This
benefit was similar in extent to being about 3 years younger in age.” The association was not restricted to women
engaging in vigorous activity. Walking the equivalent of at least 1.5 hours per
week at a 20 to 30 minute per mile pace was also associated with better
cognitive performance.
This is an interesting,
provocative study. It is not proof of any relationship between physical
activity and cognition. Observational studies cannot prove cause and effect.
But I believe patients should be reminded of the many benefits of physical
fitness. There is now suggestive evidence of improved cognitive function.
A companion
article in this issue of JAMA (pp 1447-52) “Walking and Dementia in Physically
Capable Elderly Men”, first author Robert D Abbott, University of Virginia
School of Medicine, Charlottesville, comes to the same conclusion. RTJ
9-2 COST-RELATED MEDICATION UNDERUSE
Patients often restrict their use of prescribed
medications because of cost. Those who have chronic conditions, and require
long-term medication are most vulnerable. Underuse has been associated with
serious health consequences, increased emergency department visits and nursing
home admissions, and decrements in self-reported health status.
This nationwide survey identified of a group of
patients with chronic illnesses who reported underuse of medication and the
reasons for underuse, mostly due to costs. About 1/3 never discussed this
problem with their doctors. Most patients were never asked about cost problems.
When patients did talk about the costs, the majority found the conversation
helpful. However, many stated their prescription was never changed to a generic
or to a less expensive alternative. They received no information about which
drug(s) might be less necessary and might be excluded. Few patients were given
other forms of assistance such as referral to a social service agency,
information about programs that help pay drug costs, or where to purchase less
expensive medication.
“Very few chronically ill patients who restrict their
medication use because of cost appeared to be receiving assistance from their
health care providers.”
“Clinicians should take a more proactive role in
identifying and assisting patients who have problems paying for prescription
drugs.”
Clinicians
consider the benefit/harm ratio of all drugs they prescribe. I believe the
ratio is better expressed as benefit/harm-cost. When a prescribed drug is
expensive it would be appropriate to mention this to even the most affluent
patient. And to routinely discuss cost considerations with those less
economically advantaged. Rapport with social services is most helpful.
This study
raises a most important consideration in these days of patient-centered
medicine. When negotiating a treatment plan with the patient, we must arrive at
a conclusion which the patient understands and is willing and able to follow.
An expert consultation is worthless if the patient cannot or will not follow
the prescription for any reason, including costs.
I believe
most doctors have little knowledge about costs of drugs and procedures they
prescribe. They should learn. The lowest cost effective and safe program should
be offered to all patients, regardless of their economic status.
I am
convinced the American public is over-charged and over-medicated.