MEDICAL SUBJECT HEADINGS
HIGHLIGHTS-INDEX
WHAT I WOULD DO
DIFFERENTLY BASED ON THE JANUARY-JUNE 2004 ARTICLES
· Administer a high dose of a stain drug immediately (with aspirin) for a patient with suspected acute coronary syndrome. [6-1]
· Discourage long-term use of donepezil and memantine for treatment of Alzheimer’s
· Advise smokers that they are at increased risk of macular degeneration. [3-9]
· Consider aromatase inhibitor therapy for breast cancer [3-9]
· Use estrogen-progestin hormone replacement therapy more freely in younger healthy postmenopausal women for symptom control [3-3]
· Use estrogen alone in hysterectomized women for menopausal symptom control without undue concern [4-4]
· Use statin drug for primary prevention of stroke in high risk persons, and for secondary prevention in all regardless of cholesterol levels [3-7]
· Encourage fitness and loss of intra-abdominal fat in persons with the metabolic syndrome. [5-4] [6-4]
· Discourage coronary artery calcium score as a screening method for coronary disease
· Point out the “actual” causes of death to patients: tobacco, alcohol abuse, poor diet, sedentary lifestyle [3-1]
· Point out that, although the Atkin’s diet is associated with short-term weight loss, there is as yet no evidence of long-term benefit. [1-12] [5-1]
· Remember use of “ring” prophylactic therapy with neuraminidase inhibitors in the forthcoming influenza epidemic. [6-13]
· Use alendronate for years (along with vitamin D and calcium) for continued protection against osteoporosis [3-8]
· Gauge severity of symptoms and recent onset of abdominal bloating, increased abdominal size and urinary urgency as possible clues of ovarian cancer. [6-7]
· Suggest to patients who fear “shots’ that they cough when receiving the injection. [2-11]
· Be more circumspect when ordering PSA determinations [5-6] [5-7] [6-3]
· Consider tamsulosin (Flomax) adjunctive therapy for renal colic due to stone lying near the bladder [3-12]
· Consider statin therapy for patients facing elective major non-cardiac surgery [5-5]
· Consider carefully prescribing a newly introduced drug. Is it safer, more effective, less costly, or more conveniently administered than already available drugs. [6-14]
· Consider that carotid endarterectomy in asymptomatic patients with carotid stenosis is associated with significant surgical mortality and may not lead to net benefit for 2 years.
· Advise patients that compression + vein surgery is better than compression alone for chronic venous ulceration. [6-6]
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 first 6
months 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, [1-12] indicates the 12th abstract
published in the January 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.
MEDICAL
SUBJECT HEADINGS (MeSH) JANUARY-JUNE 2004
ATKIN’S
DIET (See DIETS [1-12]; [5-1])
ALENDRONATE
(Fosamax) (See OSTEOPOROSIS [3-8])
ALTERNATIVE/COMPLEMENTARY
MEDICINE
AROMATASE
INHIBITOR (See BREAST
CANCER [3-9])
BODE
INDEX (See CHRONIC
OBSTRUCTIVE PULMONARY DISEASE [3-13])
BUPROPION (See SMOKING [2-10])
CANCER (See organ: BREAST CANCER,
PROSTATE CANCER, CERVICAL CANCER, ETC. )
CAROTID ENDARTERECTOMY (See STROKE [5-11])
CHOLESTEROL (See STATIN DRUGS)
CHRONIC
OBSTRUCTIVE PULMONARY DISEASE
(COPD)
CONGESTIVE HEART FAILURE
(See HEART FAILURE)
CORONARY ARTERY CALCIUM SCORE
(See CORONARY HEART DISEASE [1-11]; [6-2])
CORONARY ATHEROSCLEROSIS
(See CORONARY HEART DISEASE)
DEEP
VENOUS THROMBOSIS (See VENOUS THROMBOEMBOLISM [6-10])
DIASTOLIC HEART FAILUE
(See HEART FAILURE [5-2]; [5-3])
DONEPEZIL
(Aricept) (See ALZHEIMER’S
DISEASE [1-6];
[6-11]; [6-12])
DUCTAL
CARCINOMA IN SITU OF THE BREAST (See BREAST CANCER [4-13])
END
OF LIFE CARE (See DEATH AND DYING)
ESTROGEN
(See HORMONE REPLACEMENT THERAPY [4-4])
FOLIC ACID (See NEURAL TUBE DEFECTS [1-10])
FONDAPARINUX (See VENOUS THROMBOEMBOLISM [6-10])
HOMOCYSTEINE
(See OSTEOPOROSIS [5-10])
LIPID-LOWERING (See STATIN DRUGS)
LOW-CARBOHYDRATE
DIET (See DIET)
MEMANTINE
(See ALZHEIMER’S DISEASE [1-6])
NATRIURETIC
PEPTIDE (See HEART
FAILURE [2-5]
NICOTINE
REPLACEMENT (See SMOKING
[2-9])
NONSTEROIDAL
ANTI-INFLAMMATORY DRUGS (NSAIDs)
OMEGA 3 FATTY ACIDS (See CARDIOVSCULAR DISEASE [1-5])
PAIN CONTROL (See CAPSAICIN [4-7])
PHYSICAL
ACTIVITY (See FITNESS)
PLAN
B (See EMERGENCY
CONTRACEPTION [6-9])
PREMENSTRUAL
DYSPHORIC DISORDER
PROSTATE SPECIFIC ANTIGEN (See PROSTATE CANCER)
PROVIGIL (See WAKEFULNESS [1-16])
SLEEP
(See WAKEFULNESS [1-16])
STRONTIUM (See OSTEOPOROSIS [1-13])
TAMSULOSIN (Flomax) (See RENAL COLIC )
THROMBOEMBOLIC
DISEASE (See VENOUS
THROMBOEMBOLISM)
TOLVAPTAN (See HEART FAILURE [4-11])
TRANSIENT
ISCHEMIC ATTACK (TIA) (See STROKE [2-2 AND 2-3]
VIRTUAL
COLONOSCOPY (See COLONOPSCOPY
[4-2])
JANUARY TO
JUNE 2004
HIGHLIGHTS
OF ABSTRACTS AND EDITORIAL COMMENTS
4-3 INTENSIVE VERSUS MODERATE LIPID LOWERING
WITH STATINS AFTER ACUTE CORONARY SYNDROMES
Enrolled over 4000 patients (mean age 58)
who had been hospitalized for an acute coronary syndrome (ACS) within the
preceding 10 days. ACS defined as acute myocardial infarction (with or without
ECG evidence of ST-elevation), or
high risk unstable angina.
Randomized to: 1) moderate-intensity
treatment with 40 mg pravastatin ( Pravachol
), or 2) high-intensity treatment with
80 mg atorvastatin (Lipitor) daily.
Mean achieved LDL-cholesterol was 95 mg/dL
in the pravastatin group and 62 in the atorvastatin group
Over 2 years, the more intensive regimen
with atorvastatin resulted in a lower risk of death and major cardiovascular
events as compared with the moderate pravastatin regimen. The NNT for 2 years
to prevent one death, myocardial infarction, angina requiring
rehospitalization, revascularization, or stroke = 53
“Although prior placebo-controlled studies
have shown that a standard-dose statin is beneficial, we demonstrated that more
intensive lipid-lowering significantly increases this clinical benefit.”
Although both drugs were “generally well
tolerated”, there were significantly more liver-related side effects with
high-dose atorvastatin. About 1/3 of all patients in both groups dropped out
over the 2 years.
“Our results suggest that after an acute
coronary syndrome, the target LDL-cholesterol level may be lower than that
recommended in the current guidelines.”
This
was a secondary prevention trial in a very high risk group. Benefits would be
considerably less if high-dose atorvastatin were used in primary prevention.
Certainly, these results cannot be extrapolated to primary prevention.
The authors
suggest that the high-dose regimen “significantly” increased clinical benefit.
Primary care clinicians must ask—is this “clinical” benefit applicable to every
day practice? Patients with an acute
coronary syndrome and their doctors must decide if one chance in 53 over 2
years is worth while, Note that harms (liver disturbance) were statistically
significant, and, I believe, as clinically significant as the reported benefits
in the high-dose patients. Cost, adverse effects, and likelihood of
discontinuation of treatment must be considered. Some patients, knowing they are at very high risk of death or recurrence, would be inclined to
accept the high-dose.
The high drop-out rate because of an adverse
event, or the patient’s preference, or “other reasons” is disturbing. This occurred despite patients’ knowledge
that they were at high risk of recurrence and death. Drop-outs would likely be
higher still in primary care practice.
Pravastatin
has the advantage of not being significantly metabolized by the P450 system in
the liver.
Thus, concern about interactions between pravastatin
and concomitantly administered drugs is much less than with atorvastatin, which
is metabolized by the P450 system. RTJ
6-1 ASSOCIATION OF STATIN THERAPY WITH OUTCOMES
OF ACUTE CORONARY SYNDROMES: The GRACE
Study
Statin drugs may have effects in addition
to their effect on lipids. These include modulation of inflammation, inhibition
of platelet function and thrombosis, and enhancement of endothelial function.
The ability of statins to immediately
affect basic pathophysiologic mechanisms has increased interest in their
potential role in acute coronary syndromes. (ACS)
This study examined the association
between previous and early in-hospital statin therapy and outcomes of ACS.
Patients who presented with an ACS who
were already taking statins were less likely to present with ST-segment
elevation MI, experience a large infarct, and have important clinical
complications, or die.
Much of the observed effect was lost if
statin therapy was not continued during hospitalization. Such patients
had
death rates similar to patients who had never received statins. Withdrawal of
statins reduces the protective effect of statin pretreatment.
In statin-naďve patients, early statin
therapy was associated with an improvement in outcomes.
Should primary care clinicians act on these
conclusions? Primary care clinicians
often act on inconclusive evidence if the putative benefit/harm-cost ratio of
the intervention is high. Although the outcomes of the study require
confirmation and further experience, I believe the benefit/harm-cost ratio of
immediate statin therapy (as of immediate aspirin therapy) for patients with
ACS is potentially high. The benefit is potentially life-saving.
The harm
and cost of short-term therapy is very low. I
would give a high-dose statin immediately on presentation of a patient with presumed ACS.
Those on
statins long-term should be continued on statins when admitted for ACS. Those
not on statins should start them immediately. And, of course, continue after
discharge.
A study “Lipid-Lowering Therapy And
In-Hospital Mortality Following Major Non-Cardiac Surgery” (See Practical Pointers May 2004 ) also
presents evidence of immediate protective effects of statins given within the
first 2 days after major surgery. RTJ
ATKIN’S DIET (See DIET [1-12]; [5-1])
4-6 ALCOHOL INTAKE AND RISK OF INCIDENT GOUT IN
MEN
Health Professionals Follow-up Study
followed over 47 000 male subjects (mean age 55 at baseline) for 12 years. None
had gout at baseline
Compared with men who did not drink
alcohol, the relative risk (RR) of incident gout increased linearly as
consumption rose from 1 drink daily (RR compared with none = 1.3) to 2.5 in
those imbibing 5 or more drinks daily.
Beer consumption showed the strongest
independent association with risk of gout. The RR per each 12 ounce serving per day = 1.49 ( Beer
is the only alcoholic beverage that contains a large amount of purine.) Consumption of spirits was also associated
with increased risk. (RR per each drink
daily = 1.15.) Wine consumption was not associated. (RR = 1.04 for each 4-ounce serving daily.)
The null association persisted regardless of the type of wine.
Risk of gout was greater in men with a
body mass index (BMI) over 25 compared with a BMI under 25:
In
subjects with a BMI under 25, RR of gout was 2.5 in heavy drinkers. In subjects
with BMI over 25, RR increased to 5.6..
“Prospective data indicate that alcohol
intake is strongly associated with incidence of gout. The risk varies substantially
with the type of alcoholic beverage. Beer confers the greatest risk, moderate
wine drinking does not increase risk.”
Both
genetic and environmental factors play a part in the pathogenesis of gout. As
with atherosclerotic disease, hypertension, obesity, and type II diabetes, gout can be considered a disease
of “civilization”—part of the epidemic of overnutrition and sedentary
lifestyles. Gout is associated with a
high intake of meat and seafood, and low intake of dairy products.. Now this study reinforces the long-observed
relation with alcohol.
As with
obesity, gout is becoming more prevalent in developing countries as they become
more
”Westernized”. . RTJ
ALENDRONATE (Fosamax) (See OSTEOPOROSIS [3-8])
ALTERNATIVE/COMPLEMENTARY
MEDICINE
All capsules of an “all natural” remedy for erectile
dysfunction (Actra-R) contained sildenafil (Viagra),
an average of about 55 mg per capsule.
Charlatanism remains alive. Nostrums fill the shelves of our pharmacies.
Fraud pervades “alternative/complementary” medicines and the “all-natural herb”
industry. Some products have been found toxic (eg, ephedra). Some are
ineffective (eg, echinacea for upper respiratory infections in children). I
remember one report of an “all natural” topical preparation for dermatitis
which was found to contain hydrocortisone. RTJ
In October 2003, the FDA approved
memantine (Namenda) for treatment of
moderate to severe AD. Memantine is a blocker of the receptor for aspartate. It
is a new class of drug.
This study hypothesized that adding
memantine (Namenda) to donepezil (Aricept ) would result in clinical
benefit and would be well tolerated.
Memantine resulted in significant statistical, but only slight clinical
benefit when added to donepezil. It appeared safe.
Investigators, as in this report, often
stress statistically significant improvement, not clinical improvement. This
may be misleading. In my view, the outcome of this study is disappointing.. The
investigators place a spin on benefits by noting the statistically significant
outcomes. This may appear to be an impressive result, but it is not clinically
important. RTJ
6-11 LONG TERM DONEPEZIL (Aricept) TREATMENT IN 565 PATIENTS WITH ALZHEIMER’S DISEASE (AD
2000)
All three available cholinesterase
inhibitors produce small improvements in cognitive and global assessments in
selected patients mild-to-moderate AD over 3-12 months. Little is known about
long-term effectiveness, or their usefulness in patients with severe AD. Nonetheless, the demand from clinicians and
patients remains strong.
This study asked whether the cholinesterase inhibitor
donepezil (Aricept) is cost effective
and produces worthwhile clinical and social improvements .
Compared with placebo, donepezil group
achieved a slightly higher score on the mini-mental-examination within the
first 36 weeks (about 1 point above baseline on a 30-point scale). Thereafter,
scores deteriorated back to baseline at 48 weeks and to minus 4 points at 112
weeks. The placebo group lost points continuously
during
the 112 weeks.
Comparatively, over 112 weeks, donepezil
group (compared with placebo) maintained a slightly better score (a fraction of
one point) despite declining in absolute terms.
Donepezil was associated with no improvement in activities-of-daily living scale at any time up to 2 years, although,
compared with placebo, decline in ADL score was slightly slower.
No significant benefits were seen vs placebo in institutionalization, progression of disability,
behavioral and psychological symptoms, psychopathology of carers, formal care
costs, adverse events, or deaths.
No evidence that costs of caring for
patients with Alzheimer’s disease in the community are reduced by
donepezil.
Any effect of donepezil on informal caregiver time is likely to be small.
Benefits of the acetylcholinesterase
inhibitor, donepezil, are “below minimally relevant thresholds”. It is not cost
effective “The disappointingly little
overall benefit from donepezil cannot be taken lightly.” Clinicians can validly question whether
other uses of scarce resources allocated for dementia would provide better
value than routine prescription of cholinesterase inhibitors.
I believe
many patients are continuing to receive CIs far beyond the time of any hope of
benefit.
COST: about $1600 per year quoted by
drugstore.com. As is often the case, the 10 mg dose costs just a few dollars
more per year than the 5 mg dose. A pill cutter may cut cost in half. There is
no statistically significant difference in effects of 10 mg vs 5 mg. Adverse
effects (eg, gastrointestinal) are greater with the 10 mg dose. RTJ
6-12 AD 2000:
DONEPEZIL IN ALZHEIMER’S DISEASE
Patients seen in everyday practice differ
from those selected for inclusion in drug-company-sponsored trials. Drug
companies use highly refined selection criteria, often include specialized
tests to aid diagnosis, restrict
allowable comorbidity and concomitant medications as well as the extent of
behavioral or functional impairment. They pay for all protocol-related care,
including medications. “Typical selection criteria for industry sponsored
trials would exclude over 90% of out-patients with mild-to-moderate Alzheimer’s
disease in California who would otherwise be eligible to receive treatment. The
controversy about effectiveness, costs, and the clinical meaning of trial
results has been fueled by the use of participants who do not represent typical
patients.”
In the trial, donepezil and placebo were
both associated with a worsening over time. The mean differences on the MMSE
and activities of daily living scale represent a delay in symptom-worsening of
about 3 months.
This commentary presents a clinically
important point. It emphasizes the gulf which may separate results of
randomized controlled trials from benefits evident in primary care practice.
There may be a large difference between results reported by a clinical trial
for AD and clinical benefits for Mr. Jones, whose family brings him into your
office because of memory loss. A practical office-based, “real world” trial is
more meaningful and convincing. Beware of “spin”. RTJ
AROMATASE
INHIBITOR (See BREAST
CANCER [3-9])
1-14 EFFICACY AND SAFETY OF LOW-DOSE ASPIRIN IN
POLYCYTHEMIA VERA
The increase in the red cell mass in PV
causes hyperviscosity of the blood, a major determinant of circulatory
disturbance. PV is associated with an increase in thromboxane synthesis. This
suggests that thromboxane-dependent platelet activation is a major cause of
thrombosis.
Thrombotic complications are a major cause
of illness and death in untreated patients.
Long-term, low-dose aspirin, used as
primary prevention, safely prevents thrombotic complications in patients with
PV. NNT to prevent myocardial infarction, stroke, major venous thrombosis,
pulmonary embolism, or death from cardiovascular causes over 3 years = 21 to
34.
Major bleeding events associated with
low-dose aspirin occurred in one in 26.
PV
is the most common of the chronic myeloprolipherative disorders. Primary care
clinicians will likely refer patients to a hematologist, but may be responsible
for long-term follow-up. RTJ
1-15 DAILY ASPIRIN—ONLY HALF THE ANSWER
Thrombosis causes much of the illness and
death in patients with polycythemia vera. No part of the vascular system is spared. Thrombosis develops in
about 40% of patients, most often before or at the time of diagnosis. Rates of
fatal thrombosis may be high.
Increased blood viscosity is a paramount
cause of large-vessel arterial and venous thrombosis. Attempts to control
erythrocytosis by phlebotomy often fail to diminish the high rate of
thrombosis.
An apparently normal hematocrit may not be normal in patients with this
disease.. A safe target is under 45% in men and under 42% in women. Viscosity
of the blood rises dramatically at hematocrit levels above 45%.
This
indicates treatment with both aspirin and adequate hematocrit control. RTJ
Age-related macular degeneration (MD) is related to smoking.
Three cross-sectional studies of over 12
000 patients reported that current smoking leads to a 3- to 4-fold incidence of
MD compared with non-smokers. Indeed, the relative risk of smoking associated
with MD is higher than the relative risk with ischemic heart disease. A
dose-response relationship has been established.
Observational studies show a protective
effect of smoking cessation on development of MD.
I was unaware of this association.
Informing patients may be a powerful incentive to quit. RTJ
BODE INDEX (See CHRONIC OBSTRUCTIVE
PULMONRY DISEASE)
2-14 HABITS (Hormonal Replacement Therapy After
Breast Cancer—Is It Safe?)
In this 2-year randomized study, 12% of
women in the HRT group experienced a new BC vs 4% in the no-HRT group. In the HRT group, 11 were local recurrences;
5 were contralateral BC; and 10 were distant metastases. In the no-HRT group 2; 1; and 5. (One in 8 women taking HRT developed
recurrence of BC vs 1 in 25 in the no-HRT group.)
Women with a history of BC should not
receive HRT. Those already receiving HRT should be advised to discontinue.
For women with history of BC, what can
be advised for menopausal-symptom relief other than HRT? The North American
Menopause Society suggests several non-hormonal therapies:
Antidepressants
venlafaxine (Effexor), paroxetine (Paxil), and
fluoxetine (Prozac; generic). Start at very low doses and gradually
increase. Cessation requires gradual tapering off.
Gabapentin
(Neurontin) may be considered in women older than 65
Clonidine
is less effective than gabapentin. RTJ
2-18 ANTIBIOTIC USE IN RELATION TO THE RISK OF
BREAST CANCER
This case-control study compared 2266
cases of primary invasive breast cancer (BC)
with 7953 matched controls without BC in regard to their use of antibiotics.
Antibiotic use was ascertained by computerized pharmacy records. Observation
period ranged from 10 years to 23 years.
Increasing cumulative days of antibiotic
use were associated with increased incident BC.
The investigators report the risk as odds
ratios of breast cancer. By this measure, the chance of developing BC in
high-dose uses of antibiotics is twice that of non-users.
Is
this a clinically important point? Certainly, other risks are more
important. To make clinical sense,
readers must take the time and trouble of converting odds ratios into absolute
risk. Few do. According to my unadjusted calculations, an
extraordinarily high use of antibiotics use was associated with a 1% higher risk of developing BC. Patients
using antibiotics for less than 500 days (the great majority) had an increased
risk of 2 in 1000. Editors and investigators should plainly state absolute
risks in their discussion. And editors should insist upon it. RTJ)
Aromatase is the enzyme that catalyses the
conversion of androgens to estrogens in females. Exemestane is a 3rd
generation aromatase inhibitor. It inhibits aromatization almost completely.
Exemestane therapy, begun after 2 or 3
years of tamoxifen therapy, significantly reduced risk of metastatic recurrence
and contralateral breast cancer as compared with continued tamoxifen. [NNT (3
years exemestane to benefit one patient) = 21]
This is consistent with the hypothesis
that BC frequently becomes resistant to tamoxifen within 5 years.
I
included this abstract because I believe therapy with aromatase inhibitors will
continue to improve BC survival. Primary care clinicians should be aware of
developments even though they may not be directly involved in this therapy. RTJ
4-13 DUCTAL CARCINOMA IN SITU OF THE BREAST:
Review Article
Prevalence of DCIS has markedly increased since
screening mammography has become routine
(one case detected for every 1300 screening mammograms).
DCIS consists of the clonal proliferation
of cells that appear malignant and that accumulate within the lumens of mammary
ducts. There is no evidence of invasion beyond the epithelial basement membrane
into the adjacent breast stroma. It is a precursor of invasive ductal
carcinoma.
The crucial task of pathological
assessment is to distinguish DCIS from invasive cancer. Classification remains
a challenge due to differing pathologic criteria, interobserver variability,
and the heterogeneous nature of tumor growth.
The natural history of untreated low-grade DCIS has been defined in long-term, follow-up
studies of women who underwent diagnostic biopsy in the era before widespread
screening mammography. After 10 years of follow-up, 14 to 60 percent of the
women had received a diagnosis of invasive cancer in the affected breast. Such
a risk is widely thought to justify the present treatment approaches.
Simple mastectomy is highly
effective—curing at least 98% of lesion—and is a potential treatment option for
all patients.
Women with DCIS in one breast are at risk for a second
tumor (either invasive or in situ) in the contralateral breast—about 0.5% to 1%
per year. This warrants follow-up mammography in the opposite breast.
Women with DCIS have considerable deficits in
their knowledge of the disease. Their levels of
psychological distress and fear of recurrence and death are similar to those among women
with invasive breast cancer.
Because
incidence of DCIS is related to hormone replacement therapy, and is benefited
by tamoxifen, I would guess that aromatase-inhibitor therapy would be
efficacious. Undoubtedly, studies will be forthcoming.
The
generally favorable prognosis should be emphasized. Women with DCIS should be
repeatedly reassured.
This is an important responsibility for primary care
clinicians. RTJ
BUPROPION (See SMOKING [2-10])
CANCER (See organ:
BREAST CANCER, PROSTATE CANCER,
CERVICAL CANCER, ETC. )
4-7 SYSTEMATIC REVIEW OF TOPICAL CAPSAICIN FOR
THE TREATMENT OF CHRONIC PAIN
Six randomized, double-blind, placebo
controlled trials (656 patients) compared topically applied capsaicin (0.075%)
with placebo in adults with neuropathic conditions. And 3 trials (368 patients)
reported use of capsaicin (0.025%) in patients with musculoskeletal
conditions.. Capsaicin was applied 3 times daily
Patients had moderate or severe chronic
pain.
Primary outcome = number of patients with
at least 50% reduction in pain.
At 8 weeks, for those with neuropathic
pain the relative benefit of capsaicin vs
placebo was 1.4. NNT = 6. (Ie, one of 6 patients would achieve a
reduction in pain of 50%.) At 4 weeks,
for those with musculoskeletal pain, the relative benefit of capsaicin vs placebo was 1.5. NNT
= 8.
There was a substantial response to
placebo—25% to 42%.
Topical capsaicin maybe useful as an
adjunct or sole therapy for a small number of patients who are unresponsive to,
or intolerant of, other treatments.
“Systematic Review of Topical Rubifacients Containing Salicylates for the Treatment of Acute and Chronic Pain”, a companion article in this issue of BMJ (pp 995-98), reports efficacy for musculoskeletal pain was moderate to poor. Adverse effects were rare. There was, however, a lack of good clinical trials.
I believe, in some patients topical
applications may be helpful. No way to find out without trying.
First inform the patient about possible benefits and
harms. Over-the-counter availability is a plus. The placebo effect is an added
benefit. RTJ
1-5 OMEGA 3 FATTY ACIDS AND CARDIOVASCULAR
DISEASE—Fishing For A Natural Treatment
Omega 3 fatty acids from fish and fish oils can
protect against coronary heart disease.
In this era of polypharmacy, many persons believe that simple dietary
interventions or nutritional supplements may be a more natural and acceptable
method of providing benefits.
The
American Heart Association recommends:
Patients
without documented CHD should eat a variety of fish (preferably oily) at least
twice weekly. Diet should also include vegetable oils.
Patients
with documented CHD should consume 1 g of O3FA and O6FA daily.
Physicians
may prescribe 2-4 g/d of O3FA and O6FA daily, provided as capsules, for
patients with hypertriglyceridemia.
Two large randomized trials have evaluated adverse
cardiovascular effects of hormone replacement therapy (HRT) in postmenopausal women. The average age of the subjects in
these two studies was 63 years, well past onset of the menopause. Overall, the
studies concluded that HRT results in net harms.
The greatest risk of adverse effects occurred in the first year.
This was contrary to older observational studies which reported
considerable benefit in reducing cardiovascular morbidity and mortality. It led
to reevaluation of the use of HRT.
It is important to determine if adverse events occur in younger women. Most women with menopausal symptoms take HRT at an
earlier age, relatively soon after the menopause. This article reviewed 2 other
large clinical trials of younger women (mean age 54). It asks—What is the risk of adverse events at this age?
Conclusion: In young, healthy postmenopausal women, the adverse effects of
HRT on the cardiovascular system in the
first year of use were no greater than the expected harms in women not
taking HRT.
What should
primary care clinicians advise their patients about HRT?
A. Risks of
adverse events during the first few perimenopausal years are low in younger,
healthier women taking combined HRT, and even lower in those taking estrogen
alone.
B. These
risks can be further reduced by therapy aimed at reducing cardiovascular risk:
smoking cessation, low-dose aspirin; lipid, weight, and BP control; and using
the lowest effective dose of estrogen and progesterone. Indeed, I believe it
likely that women who, at the age of 50 adopt these protective measures and
take HRT will be less likely to experience cerebrovascular events than women who
do not take HRT and do not adopt these protective measures.
I believe
that recent reports overemphasized the adverse effects of HRT, and that many
women who would benefit by symptom relief are being denied treatment. RTJ
In a large group of patients at high risk of vascular disese, statin
therapy rapidly reduced risk of ischemic stroke with no apparent increase in risk
of hemorrhagic stroke. Benefits occurred
even among those who did not
have high cholesterol concentrations. Statin therapy also reduced the risk of
major vascular events among people who had previously experienced a stroke or
other cerebrovascular event.
A reduction in LDL-cholesterol from about
154 mg/dL to about 115 mg/dL reduced risk of stroke and other major vascular
events by about one-quarter. Lowering it from about 115 mg/dL to about 77 mg/dL
also reduced risk by about one quarter.
“Current guidelines could, therefore, lead to substantial undertreatment
of high-risk patients who present below, or close to, particular targets for LDL
reduction.”
“These results have important implications
for revising treatment guidelines which do not currently take into account
cerebrovascular disease risk reduction when considering the initiation of
statin therapy.”
“Statin therapy should now be considered routinely for all
patients at high risk of stroke, irrespective of their initial cholesterol
concentrations. “
This
study confirms the widely-held belief that statin therapy reduces risk of
stroke as well as coronary disease. It also strengthens the observation that
lowering LDL-cholesterol below levels usually considered “satisfactory” will
further reduce risk of atherosclerotic disease.
The risk of
events associated with cardiovascular risk factors increases linearly. There
are no artificial cut-points dividing “satisfactory” levels vs “unsatisfactory”
levels. RTJ
3-11 URIC ACID AND DIET—INSIGHTS INTO THE
EPIDEMIC OF CARDIOVASCULAR DISEASE.
The effects of diet are relevant to the
epidemiology of hyperuricemia and gout. Gout and obesity have become epidemic
among native people, such as the Maori of New Zealand, since the introduction
of Western culture and diets. The immigration of non-Western peoples to Western
countries—for example that of Filipino and Japanese to North America—has been
associated with increases in the incidence of gout in parallel with the shift
in diet to higher intakes of meat and saturated fats. Gout was rare among
blacks in the USA until the 1940s when changes in diet led to the rapid
development of obesity, diabetes, and hypertension. Now, gout is more common
among blacks than in whites. It is also becoming more common in urban
communities of Africa in association with an increasing frequency of
hypertension and cardiovascular disease.
Gout is no longer a disease of the
wealthy; rather its appearance reflects a worldwide increase in fatty meats and
a decrease in intake of dairy products associated with Westernization.
Gout should be considered a part of the
current epidemic of obesity, hypertension, and diabetes.
The
preceding articles convincingly reinforce the view that lifestyle is indeed
important in the pathogenesis of gout. RTJ
4-4 EFFECTS OF CONJUGATED EQUINE ESTROGEN IN
POSTMENOPAUSAL WOMEN WITH HYSTERECTOMY
This study reports the conjugated equine
estrogen (CEE)-alone phase of the
Women’s Health Initiative trial which was continued for 7 years. Mean baseline
age = 63.
The burden of incident disease events was
equivalent in the CEE-alone and placebo groups. There was no significant
difference in risks other than a slight increase in incidence of stroke. The
absolute excess was 12 additional
strokes per 10 000 person-years. And an absolute reduction of hip fracture of 6 per 10 000 person-years.
The estimated excess risk for all
monitored events (CHD, stroke, pulmonary embolism, colorectal cancer, hip
fracture, and deaths from other causes). was a non-significant 2 events per 10
000 person-years.
This differs importantly from the WHI
trial of combined estrogen/progestin in which the risk of CHD was significantly
elevated.
Women and their health-care professionals
now have usable risk estimates for the benefit/harm ratio of
CEE-alone
in treatment of menopausal symptoms. “Women can be reassured that incidence of
CHD and breast cancer is not increased at least for 6.8 years”. But, the data reinforce that there is no
overall benefit of CEE for chronic disease prevention.
Nevertheless, CEE-alone cannot be recommended for disease prevention. CEE should be used only for
menopausal symptoms at the smallest effective dose for the shortest possible time.
The
study reported a lower risk of breast caner in the CEE-alone group vs the placebo group This is contrary to other
observational studies in which risk of BC is increased. I believe clinicians
should remain wary and should consider that HRT in any form increases risk of
breast cancer.
I believe
risks of CEE-alone as well as combined estrogen/progestin have been
overemphasized, and that many women are being unnecessarily denied relief from
their menopausal symptoms. RTJ
The estimated prevalence of the “metabolic”
(“insulin-resistance”) syndrome is over 20% among adults in the USA.
Middle-aged men with the metabolic syndrome have significantly elevated risk of
all-cause and cardiovascular disease (CVD)
mortality.
It is defined by the National Cholesterol Education Program among persons with 3 or more
of 5 risk factors:
1. BP at or over 130/85
2. Central obesity—waist
circumference > 40 inches in men
3. High triglyceride levels—>150
mg/dL
4. Low HDL-cholesterol— < 40
mg/dL
5. High fasting plasma glucose—at or
above 110 mg/dL
After adjustment for age, smoking status, alcohol
consumption, and parental CVD, the relative risks (RR) of all-cause mortality and CVD mortality were higher in men
with the metabolic syndrome who were unfit compared with the fit men. (RR = 2.0
and 2.3)
There was a graded increase in deaths according to
fitness categories. Men in the middle tertile of fitness had 2.0 times the CVD
death rate as those in the upper tertile of fitness Those in the lower tertile of fitness had 3.5 times the risk.
The estimated population-attributable risk for CVD
deaths in males with the metabolic syndrome is 11%. This suggests that about 1 in 10 CVD deaths are directly
attributable to the metabolic syndrome. The public health burden is
considerable.
Low cardio-respiratory fitness was an important risk
factor for premature mortality in men with the metabolic syndrome. Being fit
provides a strong protective effect.
As expected,
physical fitness attenuated risk of death in men without the metabolic syndrome
as well as those with. I omitted this data.
The study is
a reminder of the definition of the metabolic syndrome and its importance as a
health risk. I have to periodically jog my memory about the definition lest I
forget the 5 requirements. Not all 5 risk factors carry equal weight.
Fitness
also attenuates risks of adverse outcomes in smokers; and in patients with
obesity, coronary disease, hypertension, and diabetes. It is a basic health
measure about which we continue to advise patients, but which they do not often
follow. RTJ
CAROTID ENDARTERECTOMY (See STROKE [5-11] )
CHOLESTEROL (See STATIN DRUGS)
CHRONIC OBSTRUCTIVE
PULMONARY DISEASE (COPD)
A simple multidimensional grading system
predicted risk of death better than the FEV1 alone.
B
Body mass index (Low BMI— weight
in kg/height in meters 2; cutpoint under 21)
O
FEV1 as a percentage of predicted
(Obstruction)
D
Score on a dyspnea scale (Dyspnea scale 0 to 4)
E
Distance walked in 6 minutes. (Exercise)
This simple grading system is a better
predictor of death from any cause and death from respiratory causes than the
FEV1 alone. Mortality increased progressively with quartiles of the score. The
highest quartile (score = 7 to 10) was associated with a mortality of 80% over
4 years.
Despite its importance as a public health
problem, COPD is vastly underappreciated. It is underdiagnosed, and when
diagnosed, is commonly undertreated. Although it is not a single entity, all
patients share a common physiological abnormality—limitation of expiratory
airflow. It is a complex disorder, affecting far more than a single organ
system. Patients with a similar FEV1 can have obvious and marked differences in
body habitus, exercise performance, and oxygenation. Additional information
complements the assessment by spirometry alone.
I believe
primary care clinicians will rarely calculate this index. They will rely for
prognosis on their general assessment of the patient. A patient who is wasted
down from his normal weight to a BMI under 21 (probably, in old parlance, a “pink puffer”), who can do
little without dyspnea, and who cannot walk even slowly for 6 minutes without
stopping, has a very dim prognosis indeed. Assessment of the general condition
may lead primary care clinicians to advise oxygen at an earlier stage, to treat
more vigorously with inhalation therapy, and to use antibiotics earlier and
more frequently. RTJ
Korean investigators recently reported
derivation of stem cells from a cloned human embryo. This may lead to
development of ability to study genetic diseases in entirely new ways.
“Experience will be needed to learn how such cells should best be used.” The
investigators strongly condemned efforts to clone a human.
4-12 COMPUTED TOMOGRAPHIC COLONOSCOPY (VIRTUAL
COLONOSCOPY)
This study assessed the accuracy of CTC vs conventional colonoscopy in a large
number of participants.
45% to 61% of the lesions were
missed by CTC. (False negative
tests.) 10% of the CTC patients were diagnosed
falsely as having a 6 mm or larger lesion. (False positive tests)
Accuracy to CTC varied considerably
between centers.
Patients expressed no clear preference for
either technique.
CTC is not yet ready for widespread clinical
application.
I abstracted this article mainly because
enthusiasts in local communities are investing in costly scanners and
advertising CTC to the general public as well as to professionals.
A study
abstracted in Practical Pointers December 2003 (12-10) reported the experience
of the Uniformed Services University of Health Sciences. This group has had
considerable experience with CTC, and uses sophisticated equipment. They
claimed that CTC detects polyps of 6 mm or larger as accurately as conventional
colonoscopy. If a polyp of this size is detected, conventional colonoscopy is
required to remove it.
A critical
issue remains. Should all polyps
detected be referred for conventional colonoscopy? If not, what is the
cut-point size? How should smaller
polyps be followed? Patients with smaller polyps (not removed) would be
required to undergo screening at shorter intervals than patients whose polyps
are removed.
As noted,
the bowel-cleansing preparation is the same in both procedures. In
observational studies, arrangements for immediate conventional colonoscopy can
be made beforehand. In usual practice settings, many patients would require a
second bowel cleansing.
I do not
believe community-based primary care clinicians should advocate CTC at this
time. RTJ
CONGESTIVE HEART FAILURE (See HEART FAILURE)
6-9 WAITING FOR
PLAN B—THE FDA AND NONPRESCRIPTION ON EMERGENCY CONTRACEPTION
The proposal to switch to levonorgestrel
emergency contraception (EC; Plan B) to over-the-counter status is
in limbo. In May, the FDA rejected the
application for non-prescription sales. The acting director, wrote that the
company had “not provided adequate data to support a conclusion that Plan B can be used safely by young
adolescent women for emergency contraception without the professional
supervision of a practitioner licensed by law to administer the drug”. In
rejecting the application, the FDA also rejected the advice of its medical
review-staff. (A vote of 23 to 4 in favor of nonprescription status.)
I would be
willing to wager that this decision will be reversed. RTJ
CORONARY ARTERY CALCIUM SCORE (See CORONARY HEART
DISEASE [1-11]; [6-2] ))
CORONARY ATHEROSCLEROSIS (See CORONARY HEART
DISEASE)
1-5 OMEGA 3 FATTY ACIDS AND CARDIOVASCULAR
DISEASE—Fishing For A Natural Treatment
Omega 3 fatty acids (O3FA) from fish and fish oils can protect against coronary heart
disease (CHD). In this era of
polypharmacy, many persons believe that simple dietary interventions or nutritional
supplements may be a more natural and acceptable method of providing benefits.
The American
Heart Association recommends:
Patients
without documented CHD should eat a variety of fish (preferably oily) at least
twice weekly. Diet should also include vegetable oils.
Patients
with documented CHD should consume 1 g of O3FA and O6FA daily. Physicians may prescribe 2-4 g/d of O3FA and
O6FA daily, provided as capsules, for patients with hypertriglyceridemia.
In an intermediate-to-high-risk cohort of
patients with coronary risk factors, the risk of a non-fatal MI or CHD death in
those with a FRS risk score over 20% was 14 times that of those with a FRS of
less than 10%.
The CACS significantly modified the risk
prediction in all categories of the FRS score of at least 10%,
but
not when the FRS was less than 10%. When the CRCS was more than 300, the
increment in predicted risk was equal to a 3% to 9% increase in the 10-year
event risk compared with FRS alone for every category of FRS estimate. The risk
of a non-fatal MI or CHD death in those with a CACS over 300 was 4 times that
of participants with a CACS of zero.
Would
adding CACS determination modify my approach to the patient? I believe it would have no effect. My advice about risk-factor control would
remain the same as that predicted by the FRS alone.
Primary
care clinicians have a broad base of risk factors to estimate prognosis. We do
not yet adequately apply them to individual patients. I do not believe adding
another factor will bring any clinical advantage. RTJ
Is there any benefit in lowering LDL-cholesterol below
the recommended 100 mg/dL?
This study, in patients with established
coronary atherosclerosis, compared the effect of moderate lipid-lowering by 40 mg pravastatin (Pravachol) with intensive
lowering by 80 mg atorvastatin (Lipitor). Final mean LDL-c was 110 in the Pravachol group and 79 in the Lipitor
group.
The main outcome (progression of coronary
atherosclerosis as determined by intracoronary ultrasound) favored
atorvastatin. Over 18 months, the atherosclerotic burden in the Pravachol group increased by +2.7%
compared with – 0.4% in the atorvastatin group.
“These findings have considerable
implications for treatment guidelines for patients with dyslipidemia and
established CAD.”
Note
this was a study of lipid-lowering and atherosclerotic progression in patients
with established CHD (a high risk group). It did not report any clinical
benefits. The extent of coronary atherosclerosis is not the most important
determinant of occurrence of acute coronary syndromes, plaque instability is.
The larger
problem of primary prevention is unanswered.
The
benefit/harm-cost ratio of intensive statin therapy is not known.
We are
becoming a nation of statin takers. Should the recommended dose be the highest
demonstrated to produce surrogate end-point benefits? Should primary care
clinicians now recommend 80 mg of atorvastatin for all? I believe not. The excess cost would be
considerable. And, despite the report that the drug “was well tolerated”, there
will be serious adverse effects. Indeed,
higher doses of all statins are related to higher risk of adverse effects.
Note that
LDL-c reached a level below 100 mg/dL in 65% of the group receiving 40 mg
Pravachol. I believe it reasonable to start with a moderate dose and gradually
increase if needed.
6-2 THE SEARCH FOR
THE “HOLY GRAIL” OF CLINICALLY SIGNIFICANT CORONARY ATHEROSCLEROSIS.
In some individuals, coronary
atherosclerosis (CA) is stable for
years, and in others it is very unstable, with rapidly progressive lesions that
result in sudden death or an acute coronary syndrome. The diagnostic “Holy
Grail” of coronary atherosclerosis is not
to be able to identify coronary atherosclerosis (which almost all Americans
have eventually) but to identify individuals with unstable coronary atherosclerotic lesions.
The editorialist describes the evolution of our
understanding the pathophysiology of CA—from the concept of a gradual process
that over decades narrows the arteries, to silent CA diagnosed by treadmill
exercise testing, to coronary angiography, and finally to efforts to detect
unstable plaques.
More myocardial infarctions occur in the larger
sub-population with negative results on a treadmill test than in those with
positive results. More myocardial infarctions are caused by hemodynamically
insignificant lesions than from high grade stenosis.
This
editorial was written in response to a meta-analysis in this issue of Archives
(pp 1285-92) which concluded that the coronary artery calcium score detected by
electron-beam computed tomography is an independent predictor of coronary
events.
The point
of the editorial was to state that fast computed tomography as a screening tool
is not ready for prime time. While scanning may reveal calcification,
individuals with unstable coronary disease are not always identified. A patient
with potentially unstable coronary atherosclerotic lesions may have mildly
calcified or non-calcified arteries. Patients with stable and unstable coronary
atherosclerosis may have similar calcium scores.
Prevention
of an essentially universal disease must be universal. Must we wait for
screening tests to detect “higher risk”, and only then encourage patients to
change his or her lifestyles?
Abdominal obesity (increased abdominal subcutaneous
fat, and increased visceral fat) is
associated with insulin resistance and other risk factors for coronary
heart disease (CHD).
This study asked: Which of these fat deposits is associated
with insulin resistance and increased risk of CHD?
Liposuction in 15 grossly obese women reduced volume
of subcutaneous abdominal fat by 44%. Weight loss = 10 kg; total body fat
decreased by 18%.
Liposuction
did not significantly alter insulin sensitivity (assessed by stimulation of
glucose uptake in muscle); did not suppress glucose production by the liver;
and did not suppress lipolysis of adipose tissue.
Levels of C-reactive protein and other indicators of
inflammation did not change.
Other risk factors for CHD were unchanged (BP, plasma
glucose, insulin, and lipid concentrations).
Large-volume reduction in subcutaneous abdominal fat
mass did not have any beneficial metabolic effects
despite
a considerable decrease in body weight, waist circumference, and plasma leptin
concentrations.
This provides insight into the mechanism by which
conventional weight loss improves insulin sensitivity.
Induction
of a negative energy balance, not simply a decrease in the mass of fat tissue,
is critical for achieving the metabolic benefits of weight loss. Even small
amounts of weight loss induced by a negative energy balance affect many
variables pertaining to body-fat composition and lipid metabolism—variables
that contribute to metabolic abnormalities associated with obesity.
Conventional weight loss decreases visceral fat mass, intrahepatic fat,
fat-cell size, and the rate of release of fatty acids from intra-abdominal
adipose tissue. Liposuction does not.
Fat loss by conventional obesity treatment
decreases plasma concentrations of C-reactive protein, interleukin-6, and tumor
necrosis factor. It improves insulin sensitivity and inhibits vascular
inflammation.
I abstracted
this article mainly to point out the risks associated with intra-abdominal fat
accumulation. Visceral fat drains directly into the portal circulation and into
the liver; subcutaneous fat drains into the general circulation. There is a
vast metabolic difference. RTJ
This article is based on a collection of
essays edited by Allen Kanner and Tim Kasser--Psychology and Consumer Culture: the Struggle for a Good Life in a
Materialistic World.
“A culture of consumption, which exalts the
acquisition of material goods over almost all other values, is causing severe
psychological harm” “People who orient their lives in pursuit of the goals that
consumer society tells us to pursue are less happy.”
People who are materialistic report less
satisfaction with life, less feeling of vitality, and lower energy compared
with those who prize “intrinsic” values (personal development, family
relationships, and community involvement). They report more problems with
depression, anxiety, and alcohol and tobacco use.
Conversely, people who place a higher
value on self-knowledge, family, and friendship, are happier and have higher
quality relationships, and a greater sense of freedom.
Since the 1950s, as our economy has grown,
happiness has not changed at all. And depression and anxiety have gone up. More
wealth is not going to make us happier.
It’s about improving other aspects of our world.
I
asked myself—Why did I abstract this article?
What has it to do with primary care medicine? I am not sure of the
answer. Perhaps it may provide some guidance to physicians and their families.
It may enable some primary care clinicians to provide guidance to troubled
patients. RTJ
3-1 ACTUAL CAUSES OF DEATH IN THE UNITED STATES,
2000
This article defines the “actual” causes of death as
underlying-modifiable-behavioral risk factors which predispose to the “disease”
which is labeled as the cause of death.
About half of all deaths could be
attributed to a limited number of largely preventable behaviors: tobacco, poor
diet and physical inactivity, alcohol, firearms, sexual behavior, and illicit
drug use.
Interventions to prevent and increase
cessation of smoking, improve diet, and increase physical activity must become
a much higher priority in the public health and health care systems.
The most striking finding is the
substantial increase (to about 400 000) in the number of estimated deaths
attributable to poor diet and physical inactivity. The gap between deaths due to poor diet and inactivity and those
due to smoking has narrowed substantially. “It is clear that if the increasing
trend of overweight is not reversed over the next few years, poor diet will
likely overtake tobacco as the leading cause of mortality.”
In addition to premature death, years of
lost life, diminished productivity, and decreased quality of life are strongly
associated with the actual causes.
One
important cause of death not directly related to obesity is the deficiency of calcium and vitamin D in the
American diet. This leads eventually to death and disability as a complication
of hip and other fractures.
Primary
care clinicians bear a responsibility and opportunity to: 1) follow a healthy
lifestyle themselves as an example to patients, and 2) to constantly encourage patients to do likewise. RTJ
3-2 THE IMMEDIATE VS THE IMPORTANT
“One of the most difficult challenges is
to ensure that the urgent does not crowd out the important. That challenge is especially difficult
because urgent matters can be so riveting.”
Every death has a definable history that
usually can be traced back to decades and sometimes even generations. Reporting
of deaths, diseases and disabilities in traditional diagnostic categories tend
to obscure the importance of factors that often play determinant antecedent
roles in the occurrence of reported conditions. When it comes to ranking health
problems and committing resources, attention seems more naturally drawn to the
conditions most proximate to serious illness or death.
5-9 DYING AND DECISION MAKING—Evolution Of
End-Of-Life Options
The editorialist reviews decision-making
options at the end of life:
Option Legal
Status Ethical Consensus Decision maker
1. Proportionately intensive symptom management Legal Consensus Patient or surrogate.
2. Stopping (or not starting) potentially life-
saving therapy Legal Consensus Patient or surrogate
3. Sedation to unconsciousness to relieve
intractable symptoms Legal Uncertain Patient or surrogate
4. Voluntarily stopping eating and drinking Legal Uncertain Patient
only
5. Physician-assisted suicide Illegal Uncertain Patient only
(except in Oregon)
The
first question to ask—Is the patient mentally competent to make decisions about
care? If so, this simplifies the
problem. If not, decisions fall on surrogates and become much more difficult.
RTJ
DEEP VENOUS THROMBOSIS (See VENOUS THROMBOEMBOLISM
[6-10])
4-2 PHARMACOLOGIC LIPID-LOWERING THERAPY IN
TYPE 2 DIABETES
Most adverse outcomes from diabetes are
due to vascular complications, either micro-vascular or macro-vascular.
Macro-vascular complications are more common and severe. Up to 80% of patients
with type 2 diabetes will develop or
die of macrovascular disease. Associated costs are 10 times greater than for
microvascular complications.
The foremost goal of therapy in type 2
diabetes should be prevention of cardiovascular disease through optimization of
risk factors. This includes aggressive treatment of hypertension,
lipid-controlling therapy, smoking
cessation, and use of daily aspirin.
Current evidence suggests that lipid
control leads to about a 25% reduction in major cardiovascular events.
For primary prevention (statins vs no
statin in patients without established cardiovascular disease) the NNT over 4
years to prevent one cardiovascular event = 35; for secondary prevention the
NNT = 14 to prevent one event over 5 years.
“Given the absolute risk reductions
observed, treatment will probably be cost-effective under most
circumstances.” This simplifies and
reduces the cost of treatment, and would be similar, for example, to simply
prescribing a daily aspirin for a patient with diabetes.”
Statins for all patients with
diabetes? This article comes close to
this recommendation. RTJ
This study
presents a simplifying common- sense clinical approach. for primary care. We
need more guidelines like this. RTJ
Insulin can be effective given by inhalation. Two
versions, a powder and an aerosol, may be nearing launch.
The bioavailability is 10-15%. The dose equivalent is
about three times that of injected insulin. Advantages of inhaled insulin
relate to patient preferences. It may improve compliance and result in more
patients achieving glycemic control.
Abdominal obesity (increased abdominal subcutaneous
fat and increased visceral fat) is
associated with insulin resistance and other risk factors for coronary
heart disease (CHD).
This study asked: Which of these fat deposits is associated
with insulin resistance and increased risk of CHD?
Liposuction in 15 grossly obese women reduced volume
of subcutaneous abdominal fat by 44%. Weight loss = 10 kg; total body fat
decreased by 18%.
Liposuction did not significantly alter insulin
sensitivity (assessed by stimulation of glucose uptake in muscle); did not
suppress glucose production by the liver; and did not suppress lipolysis of
adipose tissue.
Levels of C-reactive protein and other indicators of
inflammation did not change.
Other risk factors for CHD were unchanged (BP, plasma
glucose, insulin, and lipid concentrations).
Large-volume reduction in subcutaneous abdominal fat
mass did not have any beneficial metabolic effects
despite
a considerable decrease in body weight, waist circumference, and plasma leptin
concentrations.
This provides insight into the mechanism by which
conventional weight loss improves insulin sensitivity.
Induction
of a negative energy balance, not simply a decrease in the mass of fat tissue,
is critical for achieving the metabolic benefits of weight loss. Even small
amounts of weight loss induced by a negative energy balance affect many
variables pertaining to body-fat composition and lipid metabolism—variables
that contribute to metabolic abnormalities associated with obesity.
Conventional weight loss decreases visceral fat mass, intrahepatic fat,
fat-cell size, and the rate of release of fatty acids from intra-abdominal
adipose tissue. Liposuction does not.
Fat loss by conventional obesity treatment decreases
plasma concentrations of C-reactive protein, interleukin-6, and tumor necrosis
factor. It improves insulin sensitivity and inhibits vascular inflammation.
I abstracted
this article mainly to point out the risks associated with intra-abdominal fat
accumulation. Visceral fat drains directly into the portal circulation and into
the liver; subcutaneous fat drains into the general circulation. There is a
vast metabolic difference. RTJ
6-5 THERMODYNAMICS, LIPOSUCTION, AND METABOLISM
Hyperglycemia improves rapidly during caloric restriction. It outpaces the rate of weight
loss. About half of the improvements in glycemic control are achieved during
the first week of a negative energy balance, although the actual fat loss is
typically quite small. Substantial proportions of the early benefits of weight
loss on insulin resistance and hyperglycemia in type 2 diabetes may be attributed
to a negative energy balance.
Similar observations have been made
concerning hypertension. Much of the decrease in BP occurs fairly rapidly in
response to a negative energy balance. There is, however, a return toward
hypertensive levels once weight has reached a plateau.
Visceral adiposity is strongly associated with insulin
resistance. In animals, surgical resection of visceral fat tissue yields marked
and nearly immediate reduction in insulin resistance. The removal of an
equivalent amount of subcutaneous fat has little effect. The relation may be
related, at least in part, to the release of fatty acids into the portal
circulation.
Adipose tissue has endocrine
functions—synthesizing leptin, adiponectin, and cytokines such as tumor
necrosis factor, interleukin-6, and C-reactive protein.
During
World War II type 2 diabetes practically disappeared in the Netherlands. This
was related to the near starvation conditions produced by the invasion by
Germany. RTJ
DIASTOLIC HEART FAILUE (See HEART FAILURE [5-2]; [5-3] )
This article describes what might be
considered the obverse of the Atkins (high fat, low carbohydrate) diet.
The high carbohydrate-low fat diet
consisted of 18% fat; 19% protein; and 63% carbohydrate.
Subjects on the HCLF diet consumed about
600 K/cal daily less than those in the liberal control diet.
“Low-fat, high-carbohydrate diets may reduce body
weight via reduced food intake, since complex carbohydrate-rich foods are more
satiating and less energy dense than higher-fat foods.”
Food choices in the HCLF diet were limited—no sweets
and few snacks allowed.
I
doubt many free-living overweight persons would adhere to the diet for very
long.
I
consider this an interesting, but not a clinically significant study. It was
performed under strict observation. Food was provided by a metabolic kitchen.
It lasted only 12 weeks. There were few subjects.
Weight-loss
diets have become a multimillion dollar industry. There are many types of diet
and approaches to dieting. Gullible overweight persons in the USA seek a quick
fix. There is none. Most individuals gradually gain back any weight lost, regardless
of the diet. A calorie is a calorie, is a calorie, is a calorie. RTJ
3-10 PURINE-RICH FOODS, DAIRY AND PROTEIN
INTAKE, AND RISK OF GOUT IN MEN.
This study prospectively investigated the
association between dietary factors and new
cases of gout.
Higher intakes of meats and seafoods were
associated with increased risk of
gout. Higher consumption of low-fat dairy products was associated with decreased risk. Those in the highest quintile of meat intake
(beef, pork, and lamb as main dishes), compared with the lowest quintile, had
an elevated risk of developing gout (relative risk = 1.4). Each additional
daily serving of meat was associated with a 21% increase in risk
Corresponding RR associated with seafood
was 1.5. Each additional weekly serving was associated with a 7% increase in
risk.
Higher intake of total protein and higher intake of
purine-rich vegetables were not
associated with increased risk..
The investigators speculate that the risk
associated with increased meat and seafood may be greater in men who already
have gout because they have impaired renal clearance of uric acid and the
absorption of dietary purines causes a steeper increase in blood uric acid
levels than in persons with normal uric acid concentrations. (Ie, diet is
likely to be a secondary prevention measure.)
This
was essentially a primary prevention study. It provides no information on risk
of exacerbations due to dietary factors in men with established gout. The
authors, however, speculate that increased intake of meat and seafood may
increase risk of recurrence of acute gouty arthritis, and low-fat dairy
products may decrease risk. I believe it prudent for primary care clinicians to
advise these dietary limitations in patients with established gout. RTJ
3-11 URIC ACID AND DIET—INSIGHTS INTO THE
EPIDEMIC OF CARDIOVASCULAR DISEASE.
The effects of diet are relevant to the
epidemiology of hyperuricemia and gout. Gout and obesity have become epidemic
among native people, such as the Maori of New Zealand, since the introduction
of Western culture and diets. The immigration of non-Western peoples to Western
countries—for example that of Filipino and Japanese to North America—has been
associated with increases in the incidence of gout in parallel with the shift
in diet to higher intakes of meat and saturated fats. Gout was rare among
blacks in the USA until the 1940s when changes in diet led to the rapid
development of obesity, diabetes, and hypertension. Now, gout is more common
among blacks than in whites. It is also becoming more common in urban
communities of Africa in association with an increasing frequency of hypertension
and cardiovascular disease.
Gout is thus no longer a disease of the
wealthy; rather its appearance reflects a worldwide increase in fatty meats and
a decrease in intake of dairy products associated with Westernization.
Gout should be considered a part of the
current epidemic of obesity, hypertension, and diabetes.
The
preceding articles convincingly reinforce the view that lifestyle is indeed
important in the pathogenesis of gout. RTJ
Recently, the low-carbohydrate
(“low-carb”; [LC]; Atkin’s) diet has
gained recognition despite modest supportive scientific evidence of
efficacy. A popular version of this
diet recommends extreme restriction of carbohydrate intake to less than 20
grams daily. This level can induce
ketosis and weight loss.
This randomized trial compared the effects
of the LC, ketogenic diet vs a
low-fat, low-cholesterol reduced-calorie diet.
Over 24 weeks, otherwise healthy obese, hyperlipemic
persons who followed a LC diet lost more body weight and fat than those on a
low-fat diet. Triglyceride levels decreased; HDL-cholesterol levels increased.
The LDL-c increased in some subjects. “Because the low-carbohydrate diet may
adversely affect the LDL cholesterol level, it is prudent to monitor the serum
lipid profiles. . . .”
The drop-out rate in persons on the LC diet was lower.
This is important because the value of any diet depends on the degree to which
patients adhere to it over time.
Weight loss in both groups resulted from reduced
energy intake. The method of reducing energy intake differed greatly. The low
fat diet group received counseling to restrict intake of fat, cholesterol, and
energy. The LC diet group received counseling to restrict intake of only
carbohydrates, not energy. “The voluntary reduction in energy intake among
recipients of the LC diet merits future research.”
Further observation is needed to determine
the long-term (beyond 6 months) effects
of the LC diet. Weight loss may be difficult to maintain.
No matter what the diet, weight loss will vary
considerably between individuals. An editorialist suggests that we can
encourage overweight patients to experiment with various methods for weight
control, including the LC diet, as long as they emphasize healthy sources of
fat and protein and incorporate regular physical activity.
“We can no
longer dismiss the very-low-carbohydrate diets. ”
The
determining factor in diet therapy is its effect on long-term (years) weight
control. We wait results of these studies, Thus far, it seems doubtful that
many persons on the LC diet will maintain their weight loss over time.
I believe studies of the LC diet will be forthcoming as related to
diabetes, coronary disease, hypertension, and the metabolic syndrome, as well as obesity. RTJ
DONEPEZIL
(Aricept) (See ALZHEIMER’S
DISEASE [1-6];
[6-11]; [6-12])
DUCTAL CARCINOMA
IN SITU OF THE BREAST (See BREAST CANCER [4-13])
EMERGENCY
CONTRACEPTION
6-9 WAITING FOR
PLAN B—THE FDA AND NONPRESCRIPTION ON EMERGENCY CONTRACEPTION
The proposal to switch to levonorgestrel
emergency contraception (EC; Plan B) to over-the-counter status is
in limbo. In May, the FDA rejected the
application for non-prescription sales. The acting director, wrote that the
company had “not provided adequate data to support a conclusion that Plan B can be used safely by young
adolescent women for emergency contraception without the professional
supervision of a practitioner licensed by law to administer the drug”. In
rejecting the application, the FDA also rejected the advice of its medical
review-staff. (A vote of 23 to 4 in favor of nonprescription status.)
I would be
willing to wager that this decision will be reversed. RTJ
END OF LIFE CARE (See DEATH AND DYING)
ERECTILE DYSFUNCTION
(See FITNESS [6-8] ; OBESITY [6-8])
ESTROGEN (See HORMONE REPLACEMENT THERAPY [4-4])
4-5 EFFECT OF VITAMIN D ON FALLS
This meta-analysis of randomized,
controlled trials concludes that vitamin D supplementation reduces risk of
falling in elderly persons. Based on 5 of the trials in over 1200 persons,
vitamin D, was associated with a reduction in rate of falls by 22%.
In two studies, vitamin D plus calcium
(compared with calcium alone) improved body sway by 9% within 2 months, and
increased muscle function up to 11%.
What is a possible mechanism? 1,25-hydroxyvitamin
D, the active metabolite, binds to a highly specific nuclear receptor in muscle
tissue. This may mediate de novo protein synthesis through this specific
nuclear receptor leading to an increase in the number, size and strength of
muscle fibers. This benefit may occur within several months. (Too early to be attributed to increased bone
strength.)
I considered this a weak study, but
interesting. If indeed vitamin D strengthens muscle and thus prevents falls,
its benefit/harm-cost ratio (which is already high.) will be substantially
increased.
Vitamin D
and calcium intake is generally too low in the US population. I believe that
supplementation is warranted in persons of all ages to help maintain bone mass
and strength. If muscles are strengthened, so much the better. RTJ
1-1 TOTAL ENERGY
EXPENDITURE AND PHYSICAL ACTIVITY IN YOUNG SCOTTISH CHILDREN
The epidemic of childhood obesity has been
attributed largely to a decline in total energy expenditure (TEE). This study postulated that the
lifestyle of contemporary young children is sedentary.
Levels of TEE were low at ages 3 and 5 in both sexes. Lifestyles in
this sample of youngsters were sedentary. This would increase risk of obesity.
Their total energy expenditure was significantly lower than the UK estimate
average requirement for energy for children.
Children typically spent only 20-25 min per day in
moderate to vigorous physical activity. Present recommendations are that they
should accumulate at least 60 min daily. “There is a widespread perception
among parents and health and educational professionals that young children are
spontaneously active. Actually, modern children establish a sedentary lifestyle
at an early age.”
Prevalence of childhood obesity has
increased strikingly in recent years.
1-2 PHYSICAL ACTIVITY AND OBESITY
The nature of human physiology is such
that it is extremely difficult, if not impossible, to maintain a healthy
bodyweight with a low level of physical activity.
Obesity arises from an imbalance in which energy
intake exceeds energy expenditure. This means that sedentary people must
maintain a low intake of energy to avoid obesity. Human physiology did not
develop to support restriction of energy intake. It is difficult for most
people to do so consistently over time
We have to teach children (and adults) to use their
intellect to push back against the environment. Such a change can be done by
eating a little less and being a little more physically active than ordinarily.
Small changes would counter the natural tendency to succumb to the environment.
“We suggest that weight gain in 90% of the
US adult population could be prevented by reducing positive energy balance by
only 100 kcal per day.” Small and achievable changes in behavior can have a big
impact.
Removing
high fructose drinks from ready availability to youngsters is a good first
step. RTJ
The estimated prevalence of the “metabolic”
(“insulin-resistance”) syndrome is over 20% among adults in the USA.
Middle-aged men with the metabolic syndrome have significantly elevated risk of
all-cause and cardiovascular disease (CVD)
mortality.
It is defined by the National Cholesterol Education Program among persons with 3 or more
of 5 risk factors:
1. BP at or over 130/85
2. Central obesity—waist circumference > 40 inches
in men
3. High triglyceride levels—>150 mg/dL
4. Low HDL-cholesterol— < 40 mg/dL
5. High fasting plasma glucose—at or above 110 mg/dL
After adjustment for age, smoking status, alcohol
consumption, and parental CVD, the relative risks (RR) of all-cause mortality and CVD mortality were higher in men
with the metabolic syndrome who were unfit compared with the fit men. (RR = 2.0
and 2.3)
There was a graded increase in deaths according to
fitness categories. Men in the middle tertile of fitness had 2.0 times the CVD
death rate as those in the upper tertile of fitness. Those in the lower tertile of fitness had 3.5 times the risk.
The estimated population-attributable risk for CVD
deaths in males with the metabolic syndrome is 11%. This suggests that about 1 in 10 CVD deaths are directly
attributable to the metabolic syndrome. The public health burden is considerable.
Low cardio-respiratory fitness was an important risk
factor for premature mortality in men with the metabolic syndrome. Being fit
provides a strong protective effect.
As expected,
physical fitness attenuated risk of death in men without the metabolic syndrome
as well as those with. I omitted this data.
The study is
a reminder of the definition of the metabolic syndrome and its importance as a
health risk. I have to periodically jog my memory about the definition lest I
forget the 5 requirements. Not all 5 risk factors carry equal weight.
Fitness
also attenuates risks of adverse outcomes in smokers; and in patients with
obesity, coronary disease, hypertension, and diabetes. It is a basic health
measure about which we continue to advise patients, but which they do not often
follow. RTJ
6-8 EFFECT OF
LIFESTYLE CHANGES ON ERECTILE DYSFUNCTION IN OBESE MEN
Erectile dysfunction (ED) is common, even in young men. Several modifiable lifestyle
factors are associated with maintenance of erectile function. Men with a body
mass index over 28 have a 30% higher risk of ED. The prevalence of overweight
and obesity in men reporting ED may be as high as 79%, although vascular
factors associated with obesity may play an important role.
This study of obese men with ED determined if a
long-term reduction in BMI and an increase in physical activity would
positively affect erectile functions.
At 2 years an intensive dietary-fitness
program led to over 10% loss of body weight and an increase in physical
fitness. About 1/3 of the men regained erectile function.
For many patients, ED is a manifestation of more
generalized pathology. Hypertension, hyperglycemia, and dyslipidemia are common
co-morbidities. Endothelial dysfunction is likely a pathogenic mechanism common
to these co-morbid states, risk of cardiovascular disease, and ED. The study
demonstrated improvements in endothelial function related to weight loss..
This is not,
however, a practical application. Few patients in primary care practice would
be able to complete such a program
The main
message is—maintain a healthy lifestyle, don’t wait to repair damage until
after it is done. RTJ
FOLIC ACID (See NEURAL TUBE DEFECTS [1-10])
FONDAPARINUX (See VENOUS THROMBOEMBOLISM [6-10])
1-9 HELICOBACTER PYLORI ERADICATION TO PREVENT
GASTRIC CANCER IN A HIGH-RISK REGION OF CHINA
Over 7 years, in a subgroup of patients without any precancerous lesions in the
stomach, eradication significantly reduced risk of developing GC.
Other investigators suggest that
Hp-infected patients with normal findings on endoscopy are at risk of
development of GC. Therefore, in high-risk populations, all patients with H pylori infection with no precancerous
lesions should consider the use of eradication treatment for gastric cancer
prevention.
Further studies are required to determine
the role of eradication in those with precancerous lesions.
I believe
essentially all patients in the USA with demonstrated H pylori infection should
receive eradication therapy. RTJ
3-10 PURINE-RICH FOODS, DAIRY AND PROTEIN
INTAKE, AND RISK OF GOUT IN MEN.
This study prospectively investigated the
association between dietary factors and new
cases of gout.
Higher intakes of meats and seafoods were
associated with increased risk of
gout. Higher consumption of low-fat dairy products was associated with decreased risk. Those in the highest quintile of meat intake
(beef, pork, and lamb as main dishes), compared with the lowest quintile, had
an elevated risk of developing gout (relative risk = 1.4). Each additional
daily serving of meat was associated with a 21% increase in risk.
Corresponding RR associated with seafood
was 1.5. Each additional weekly serving was associated with a 7% increase in
risk.
Higher intake of total protein and higher
intake of purine-rich vegetables were not
associated with increased risk..
The investigators speculate that the risk
associated with increased meat and seafood may be greater in men who already
have gout because they have impaired renal clearance of uric acid and the
absorption of dietary purines causes a steeper increase in blood uric acid
levels than in persons with normal uric acid concentrations. (Ie, diet is
likely to be a secondary prevention measure.)
This
was essentially a primary prevention study. It provides no information on risk
of exacerbations due to dietary factors in men with established gout. The
authors, however, speculate that increased intake of meat and seafood may
increase risk of recurrence of acute gouty arthritis, and low-fat dairy
products may decrease risk. I believe it
prudent for primary care clinicians to advise these dietary limitations
in patients with established gout. RTJ
3-11 URIC ACID AND DIET—INSIGHTS INTO THE EPIDEMIC
OF CARDIOVASCULAR DISEASE.
The effects of diet are relevant to the
epidemiology of hyperuricemia and gout. Gout and obesity have become epidemic
among native people, such as the Maori of New Zealand, since the introduction
of Western culture and diets. The immigration of non-Western peoples to Western
countries—for example that of Filipino and Japanese to North America—has been
associated with increases in the incidence of gout in parallel with the shift
in diet to higher intakes of meat and saturated fats. Gout was rare among
blacks in the USA until the 1940s when changes in diet led to the rapid
development of obesity, diabetes, and hypertension. Now, gout is more common
among blacks than in whites. It is also becoming more common in urban
communities of Africa in association with an increasing frequency of
hypertension and cardiovascular disease.
Gout is thus no longer a disease of the
wealthy; rather its appearance reflects a worldwide increase in fatty meats and
a decrease in intake of dairy products associated with Westernization.
Gout should be considered a part of the
current epidemic of obesity, hypertension, and diabetes.
The
preceding articles convincingly reinforce the view that lifestyle is indeed
important in the pathogenesis of gout.
4-6 ALCOHOL INTAKE AND RISK OF INCIDENT GOUT IN
MEN
Health Professionals Follow-up Study
followed over 47 000 male subjects (mean age 55 at baseline) for 12 years. None
had gout at baseline
Compared with men who did not drink
alcohol, the relative risk (RR) of incident gout increased linearly as
consumption rose from 1 drink daily (RR compared with none = 1.3) to 2.5 in
those imbibing 5 or more drinks daily.
Beer consumption showed the strongest
independent association with risk of gout. The RR per each 12 ounce serving per
day = 1.49 (Beer is the only alcoholic
beverage that contains a large amount of purine.) Consumption of spirits was also associated with increased
risk. (RR per each drink daily = 1.15.) Wine consumption was not associated. (RR = 1.04
for each 4-ounce serving daily.) The null association persisted regardless of
the type of wine.
Risk of gout was greater in men with a
body mass index (BMI) over 25 compared with a BMI under 25:
In
subjects with a BMI under 25, RR of gout was 2.5 in heavy drinkers. In subjects
with BMI over 25, RR increased to 5.6..
“Prospective data indicate that alcohol
intake is strongly associated with incidence of gout. The risk varies
substantially with the type of alcoholic beverage. Beer confers the greatest
risk, moderate wine drinking does not increase risk.”
Both
genetic and environmental factors play a part in the pathogenesis of gout. As
with atherosclerotic disease, hypertension, obesity, and type II diabetes, gout
can be considered a disease of “civilization”—part of the epidemic of
overnutrition and sedentary lifestyles.
Gout is associated with a high intake of meat and seafood, and low
intake of dairy products. Now this
study reinforces the long-observed relation with alcohol.
As with
obesity, gout is becoming more prevalent in developing countries as they become
more
”Westernized”. There are more obese
persons in the world now than hungry persons. RTJ
2-5 B-TYPE NATRIURETIC PEPTIDE—A Biomarker For
All Seasons?
Recently, natriuretic peptides have been introduced as
biomarkers:
1) In patients presenting to the emergency
department with acute dyspnea, elevated BTNP was helpful in discriminating
between heart failure and other causes of dyspnea (chiefly COPD)
2) In asymptomatic middle-aged persons,
BTNP was prognostic of future death, heart failure, and stroke over a mean of 5
years. Levels of BTNP higher than 20 pg/mL (above the 80th
percentile) were associated with an increase of over 60% in the long-term risk
of death. There was also a significant prognostic gradient of BTNP levels - low
(under 4 pg/ml), intermediate (4 to 13), and high (over 13)—with respect to
risk of heart failure, and stroke. This is remarkable because levels below 100
pg/mL are considered to rule out heart failure.
The first use
may be of value to the primary care clinician in making triage decisions.
Regarding the
second application—investigators struggle to find more
meaningful and accurate risk markers for cardiovascular disease. I doubt BTNP
adds anything of clinical importance to risk assessment
I believe we
already have enough risk markers to act upon (and often do not) in order to improve prognosis. When the BTNP
is elevated what does one do to reduce risk? — simply revert to measurement and
treatment of the traditional risk factors.
RTJ
Levels of arginine vasopressin (AVP; the water-retaining hormone
secreted by the pituitary) are increased in heart failure (HF). Water retention and hyponatremia result.
Tolvaptan is a non-peptide, orally
administered, once daily vasopressin antagonist.
It binds predominantly with the AVP receptor in the kidney, resulting in
decreased renal vascular resistance, increased renal blood flow, improved
glomerular filtration rate, and loss of free water. Rather than being
classified as a traditional diuretic, tolvaptan is more precisely characterized
as an aquaretic.
This study assessed the clinical
effectiveness of tolvaptan in patients hospitalized for HF.
Tolvaptan, vs placebo, given in addition
to standard therapy (including diuretics) resulted in a greater net volume
loss. It produced a rapid and sustained increase of serum levels of sodium (due
to loss of free water) in patients with hyponatremia. It did not adversely
affect BP, heart rate, electrolyte levels, or renal function.
When
I started to study medicine, the treatment of HF consisted of rest, digitalis
pills, salt restriction, and the intramuscular mercury-containing diuretic,
mercuhydrin. (How many out there remember mercuhydrin? )
Therapeutic
advances have been remarkable—beta-blockers, ACE inhibitors and angiotensin II
blockers, spirinolactone, and loop diuretics, as well as use of low-dose
digoxin. Nevertheless, prognosis of patients with HF remains poor. These newer
drugs are really “rear guard” therapies. It may well be that the main benefit
of vaptans is symptomatic relief. Lessening dyspnea and edema may make patients
more comfortable. Certainly, vaptans
will make therapy easier by reducing worry about hyponatremia, hypokalemia, and
renal dysfunction.
Note, the
study assessed only systolic HF. The large issue of diastolic HF remains.
Primary
care clinicians stay tuned. RTJ
This prospective clinical study analyzed
measurement of diastolic function (pressures and volumes of the left ventricle)
in patients with HF who had a normal ejection fraction.
Patients with clinical HF and a normal ejection
fraction (50%) had abnormalities in the diastolic properties of the left
ventricle that were sufficient to explain the occurrence of HF. Pressure-volume
relations were abnormal during ventricular relaxation in earliest diastole, and
during the entire time of passive ventricular filling. The term “diastolic heart failure” can be
appropriately used to describe these abnormalities in such patients.
Increased left ventricular stiffness in
patients with diastolic heart failure makes them especially vulnerable to the
development of pulmonary edema. Significant changes in pressure may be seen
with little change in volume of the left ventricle. The ventricle is unable to accept venous return adequately
without high diastolic pressures. Such high pressures result in decreased lung
compliance, increased work of breathing, dyspnea, and exercise intolerance.
Pulmonary edema is the direct consequence of increased passive chamber
stiffness.
Patients with diastolic HF have a
substantial increase in pulmonary venous pressures during exercise and a
significant limitation in exercise tolerance. The non-compliant stiff ventricle
has limited ability to use the Frank-Starling
mechanism. During exercise, the left ventricle is unable to fill optimally, and
despite the increased filling pressure, the cardiac output cannot increase.
Exercise intolerance is the direct consequence of abnormal left ventricular
diastolic function.
I freely
interpreted the pathophysiology the authors described. I believe my interpretation to be accurate,
although the article expresses it differently and gives more details. Simply
put, in diastolic HF, for every volume of the left ventricle, pressures are
higher than normal; and for every pressure, volumes are lower than normal.
I welcomed
this article. It clarified my understanding. of diastolic HF It emphasized the importance of control of hypertension as a preventive
measure. It did not lead to any suggestions for treatment. Pathological changes
in the left ventricular myocardium are yet to be fully described. RTJ
5-3 MANAGEMENT OF DIASTOLIC HEART FAILURE IN
OLDER ADULTS
The signs and symptoms of diastolic HF are similar to
those of systolic HF. In diastolic HF, the ejection fraction remains normal
(> 50%). Both experience volume
overload. Distended neck veins are the most reliable sign of overload.
A more specific diagnosis would require
documentation of an abnormal left ventricular relaxation pattern. This is often
determined by a reduced ratio of early (E; filling immediately after the mitral
valve opens) to late (A; due to atrial contraction) filling velocities by
Doppler echocardiography The E:A ratio is reduced (<1) in advanced diastolic
HF (eg E:A < 0.5). Normal is >
1. The ratio is difficult to assess in
patients with atrial fibrillation. (Ie, in diastolic HF, the early filling is
less efficient than the late (atrial contraction) filling. The reverse is normal.)
There is little evidence from large randomized trials
to guide treatment. The author suggests some interventions.
Intraventricular conduction delay is
associated with dys-synchronous left ventricular contraction due to regional
delays in the electrical activation of the chamber. It occurs in 15% to 30% of
patients with heart failure (HF) due
to dilated cardiomyopathy. It impairs systolic function.
Patients with HF and bundle-branch block
have a mechanical disadvantage resulting from abnormal activation of the left
ventricle. In these patients, the septum contracts before the lateral left
ventricle wall. The lateral wall contracts during relaxation of the septum.
This mechanical dysfunction increases left ventricular volume, reduces
contractility, and worsens mitral regurgitation. Proper placement of the
pacemaker leads permits pacing the right ventricle, the septum, and the lateral
wall of the left ventricle simultaneously.
This study assessed the effectiveness of
CRT in patients with advanced chronic HF who had intraventricular conduction
delays. In the pacemaker group (compared with the drug-only group), CRT
resulted in a reduction of death, hospitalization, a slightly higher systolic
BP, a slight increase in distance walked in 6 minutes, and improvement in
quality-of-life and in the NYHA class.
Note—this
applies only to systolic HF.
The purpose
of the normal Purkinje subendocardial conducting system is to rapidly conduct
the electrical impulse to all parts of the ventricles so that all parts of the
myocardium contract simultaneously. CRT is a feeble attempt to mimic this
function.
In spite of
some incremental improvements in therapy of HF over the past 10 years,
prognosis remains miserable. Death and hospitalization for HF continued to
increase in the subgroup of patients followed for 3 years. In the CRT group,
only about 20% had event-free survival at 3 years, and the death rate increased from 12% at 1 year to about 30% at 3 years. Patients will welcome some
improvement in quality-of-life. RTJ
Non-selective NSAIDs are associated with an increased
risk of heart failure (HF). In susceptible individuals, they raise systemic vascular resistance and
reduce renal perfusion. BP may be elevated, and edema and HF may result.
The selective COX-2 inhibitors, celecoxib (Celebrex) and rofecoxib (Vioxx )
are reported to be associated with a lower risk of gastrointestinal
events than the non-selective NSAIDs.
Might they also be associated with fewer cardiovascular and renal
complications? Might celecoxib and
rofecoxib differ in their risks?
Relative to non-NSAID users, the rate of admission for
HF was significantly higher for users of rofecoxib (RR = 1.8) and non-selective
NSAIDs (RR = 1.4), but not celecoxib
(RR = 1.0)
Patients with a history of HF were much more likely to
be admitted for recurrent HF. Those taking celecoxib were more likely to be
readmitted than controls (RR = 1.2), but much less likely than those taking
non-selective NSAIDs (RR = 2.2) and rofecoxib (RR = 1.8)
The authors
state that , in other studies, patients with long-standing hypertension showed
greater increases in systolic BP among those receiving rofecoxib compared with
those receiving celecoxib.
We too often
concentrate on the adverse effects of NSAIDs on the gastrointestinal tract, and
forget those on the cardiovascular and renal systems.
Although
celecoxib may have a slight edge as far as adverse effects are concerned, I
would avoid its use (and that of any NSAID) in patients with a history of HF,
or at risk of HF (including diastolic HF), as well as patients with
uncontrolled hypertension. RTJ
1-9
HELICOBACTER PYLORI ERADICATION TO PREVENT GASTRIC CANCER IN A HIGH-RISK
REGION OF CHINA
Over 7 years, in a subgroup of patients without any precancerous lesions in the
stomach, eradication significantly reduced risk of developing GC.
Other investigators suggest that
Hp-infected patients with normal findings on endoscopy are at risk of
development of GC. Therefore, in high-risk populations, all patients with H pylori infection with no precancerous
lesions should consider the use of eradication treatment for gastric cancer
prevention.
Further studies are required to determine
the role of eradication in those with precancerous lesions.
I believe
essentially all patients in the USA with demonstrated H pylori infection should
receive eradication therapy. RTJ
HOMOCYSTEINE (See OSTEOPOROSIS [5-10])
2-13 TREATMENTS OF HOMOSEXUALITY IN BRITAIN
SINCE THE 1950s--AN ORAL HISTORY
In Britain, “treatments” to change homosexuals
into heterosexuals peaked in the 1960s and early 1970s. “Some participants
chose to undergo treatments instead of imprisonment.” (Sexual behavior in private between adult men was not
decriminalized in Britain until 1967.) DSM classified homosexuality as a
disease until 1973.
Treatments included behavioral aversion therapy with electroshock
(including electroconvulsive therapy) and apomorphine (one died of side
effects); psychoanalysis; estrogen to reduce libido; religious counseling; and
hypnosis.
No participant benefited from treatment.
“There is no evidence that treatments were effective at changing sexual
orientation.”
“Social and political assumptions
sometimes lie at the heart of what we regard as mental pathology and serve as a
warning for future practice.”
“Assumptions about public morality and professional authority can lead
to the medicalization of human differences and the infringement of human
rights.”
We are not
as far removed from barbarism as we think we are. (Note the eugenics movement
in the USA in the 20th century.)
In the USA
as elsewhere, social mores, religion, politics, and culture still influence
medical decisions, and override some of the established benefits scientific
medicine brings for both individuals and the general population. RTJ
2-14 HABITS (Hormonal Replacement Therapy After
Breast Cancer—Is It Safe?)
In this 2-year randomized study, 12% of
women in the HRT group experienced a new BC vs 4% in the no-HRT group. In the HRT group, 11 were local recurrences;
5 were contralateral BC; and 10 were distant metastases. In the no-HRT group 2; 1; and 5. (One in 8 women taking HRT developed
recurrence of BC vs 1 in 25 in the no-HRT group.)
Women with a history of BC should not
receive HRT. Those already receiving HRT should be advised to discontinue.
What about
HRT in women with ductal carcinoma in situ? I would be cautious in using HRT in
these patients as well.
For women with history of BC, what can
be advised for menopausal-symptom relief other than HRT? The North American
Menopause Society suggests several non-hormonal therapies:
Antidepressants
venlafaxine (Effexor), paroxetine (Paxil), and fluoxetine (Prozac; generic).
Start at very low doses and gradually increase. Cessation requires gradual
tapering off.
Gabapentin
(Neurontin) may be considered in women older than 65
Clonidine
is less effective than gabapentin. RTJ
Two large randomized trials have evaluated effects of
hormone replacement therapy (HRT) in
postmenopausal women.
The average age of the subjects in these
two studies was 63 years, well past onset of the menopause. Overall, the
studies concluded that HRT results in net harms.
. The greatest risk of adverse effects occurred in the first year.
This was contrary to older observational studies which reported
considerable benefit in reducing cardiovascular morbidity and mortality. It led
to reevaluation of the use of HRT.
It is important to determine if adverse
events occur in younger women. Most women
with menopausal symptoms take HRT at an earlier age, relatively soon after the
menopause. This article reviewed 2 other large clinical trials of younger women
(mean age 54). It asks—What is the
risk of adverse events at this age?
Conclusion: In young, healthy postmenopausal women, the adverse effects of
HRT in the first year of use were no
greater than the expected harms in women not taking HRT.
What should
primary care clinicians advise their patients about HRT?
A.
Risks of adverse events during the first few perimenopausal years are low in
younger, healthier women taking combined HRT, and even lower in those taking
estrogen alone.
B. These risks can be further reduced by therapy aimed at reducing cardiovascular risk: smoking cessation, low-dose aspirin; lipid, weight, and BP control; and using the lowest effective dose of estrogen and progesterone. Indeed, I believe it likely that women who, at the age of 50 adopt these protective measures and take HRT will be less likely to experience cerebrovascular events than women who do not take HRT and do not adopt these protective measures.
I believe
that recent reports overemphasized the adverse effects of HRT, and that many
women who would benefit by symptom relief are being denied treatment. RTJ
4-4 EFFECTS OF CONJUGATED EQUINE ESTROGEN IN
POSTMENOPAUSAL WOMEN WITH HYSTERECTOMY
This study reports the conjugated equine
estrogen (CEE)-alone phase of the
Women’s Health Initiative trial which was continued for 7 years. (Age at
baseline = 63.)
The burden of incident disease events was
equivalent in the CEE-alone and placebo groups. There was no significant
difference in risks other than a slight increase in incidence of stroke. The
absolute excess was 12 additional
strokes per 10 000 person-years. And an absolute reduction of hip fracture of 6 per 10 000 person-years.
The estimated excess risk for all
monitored events (CHD, stroke, pulmonary embolism, colorectal cancer, hip
fracture, and deaths from other causes). was a non-significant 2 events per 10
000 person-years.
This differs importantly from the WHI
trial of combined estrogen/progestin in which the risk of CHD was significantly
elevated.
Women and their health-care professionals
now have usable risk estimates for the benefit/harm ratio of
CEE-alone
in treatment of menopausal symptoms. “Women can be reassured that incidence of
CHD and breast cancer is not increased at least for 6.8 years”. But, the data also reinforce that there is
no overall benefit of CEE for chronic disease prevention.
Nevertheless, CEE-alone cannot be recommended for disease prevention. CEE should be used only for
menopausal symptoms at the smallest effective dose for the shortest possible time.
The
study reported a lower risk of breast caner in the CEE-alone group vs the placebo group This is contrary to other
observational studies in which risk of BC is increased. I believe clinicians
should remain wary and should consider that HRT in any form increases risk of
breast cancer.
I believe
risks of CEE-alone as well as combined estrogen/progestin have been
overemphasized, and that many women are being unnecessarily denied relief from
their menopausal symptoms. RTJ
4-9 ASYMPTOMATIC PRIMARY HYPERPARATHYROIDISM
The diagnosis of AHP is made on the basis
of a combination of elevated total serum calcium + an inappropriately elevated
PTH.
Criteria of
parathyroid surgery (cutoff points):
Serum calcium 1.0
mg/dL above upper normal
24-hour calcium >
400 mg
Reduction in creatinine clearance 30%
Bone mineral density T
score below -2.5 (Radius is particularly vulnerable)
Age Under
50
Surgery is routinely warranted in patients with kidney
stones.
Most patients with AHP who do not meet the
criteria for surgery do well, with no evidence of progressive disease. In most
patients, the average serum and parathyroid hormone levels do not change over
10 years. And BMD is typically stable.
Hypercalciuria usually does not worsen.
Younger patients (< age 50) are more likely to progress.
Many patients with AHP will not require
surgery. Patients who do not meet the criteria for surgery should be monitored
periodically (serum calcium, creatinine clearance, and BMD) because about 25%
of patients will progress.
To advise
surgery or advise continued surveillance is a clinical call. It depends on
patient preference and individual circumstances. If expert surgery is
available, I would tilt toward surgery. This would relieve the patient of
continuing concerns. RTJ
4-10 MINIMALLY INVASIVE PARATHYROIDECTOMY
The arrival of tecnitium-99m sestamibi
scanning revolutionized preoperative localization of parathyroid glands. It
accurately identifies the side and size of the adenoma in 9 out of 10 cases.
Patients with reliably localized single
adenomas may be treated with a minimal access approach. This is achieved
through a 2 cm incision. It can usually be done as a day case procedure in less
than 20 minutes with local anesthesia. It has become the first line treatment
in specialized units.
Primary
care clinicians, if they practice long enough, will encounter patients with
asymptomatic HPT. The advent of minimalist surgery further tilts the decision
toward operating. RTJ
Intermittent, self-measurement of BP with
an inexpensive ocillometric reader at home accomplishes several of the
advantages of 24-hour ambulatory monitoring.
This study compared BP measurements taken
in the physician’s office with those self-measured at home in patients with
hypertension. The goal was a diastolic between 80 and 89.
HomeBP led to less intensive drug
treatment and marginally lower costs. It determined presence of white-coat
hypertension (office BP higher than home BP), and led to discontinuation of
drug therapy in twice as many patients as
office BP measurement, but slightly poorer long-term BP control. It may
also help identify masked hypertension (home BP higher than office BP).
Should
primary care clinicians offer home BP recordings to their patients with
hypertension?
I believe it would be helpful. The greatest benefit
would be in eliminating or reducing drug therapy in a sizable number of
patients. It would also increase compliance and interest in treatment, and
reduce the number of office visits. The downside might be slightly less
adequate control.
BP goals
would differ depending on the individual patient. The great majority of older
patients with hypertension have isolated systolic hypertension.
Would
patients accept and comply with this approach? They might, with difficulty.
Enthusiastic support will be required. Machines would have to be recalibrated
periodically. RTJ
There are numerous criticisms of clinical
BP measurement. Major inter- and intra-observer variability exist. There are
difficulties with standardization of the measurement conditions, and
insufficiency in the number of measurements. Office BP fails to recognize the
patient’s average daily BP.
In this study, home BP self-measurement
defined the prognosis in terms of cardiovascular morbidity and mortality better
than office measurement. This was due in part to the poor performance of office
BP measurements.
The study reported a high prevalence of
two classes of patients with hypertension not recognized by BP measurements
confined to the office: 1) “White coat” hypertension (office BP higher than
home BP);
2)
“Masked” hypertension (the
opposite—home BP higher than office BP).
“The frequency of this double error, which is both diagnostic (with
respect to the control of hypertension), and prognostic (with respect to the
incidence of cardiovascular events), suggests that monitoring of patients being
treated for hypertension must include home BP self measurement.”
“Masked” hypertension was associated with
a statistically significant increase in risk of adverse cardiovascular
events. Indeed, the risk over 3 years
was about the same as the group with uncontrolled hypertension. It remains to be seen, however, that
adaptation of treatment to the
results of home BP self-measurement allows better cardiovascular prevention
than treatment based on office BP.
Although,
as the authors state, there are no data reporting outcomes of patients treated
for “masked hypertension”, I believe it would be reasonable to treat them. What
about “white coat”? Previous observations suggest that these patients are
subject to development of sustained hypertension. They should be carefully
observed. Some would advocate treatment.
I believe
home BP will become more standardized as a method for following patients
treated for hypertension. RTJ
1-7 RISKS OF TESTOSTERONE-REPLACEMENT THERAPY AND
RECOMMENDATIONS FOR MONITORING.
Hypogonadism is a clinical condition in
which low levels of serum testosterone are found in association with specific
signs and symptoms: diminished libido
and sense of vitality, erectile dysfunction, depression, anemia, and reduced
muscle mass and bone density. Prescriptions for testosterone supplementation
have increased substantially over the past decade.
Reports indicate that testosterone
replacement may produce a wide range of benefits: improvement in libido, bone density, muscle mass, body
composition, mood, erythropoiesis, and cognition.
No studies have yet been initiated to
assess benefits and risks, especially possible stimulation of prostate cancer.
But, “Despite decades of research, there is no compelling evidence that
testosterone has a causative role in prostate cancer”. There
is no compelling evidence to suggest that men with higher testosterone levels
are at greater risk of PC or that treating men with hypogonadism with exogenous
androgens increases risk. Nevertheless, the authors advocate routine biopsy in
all men presenting for replacement therapy
Should
primary care clinicians deal with this problem? Should they refer patients
seeking therapy to a urologist with considerable experience? At the present stage of development, I would
follow the second course.
The value of
a therapy has been described as: Value
= benefits
harms-costs
I believe
the benefits are somewhat nebulous and unknown long-term. Harms are potentially
great. Cost is considerable considering consultation and laboratory fees as
well as the cost of the testosterone.
RTJ
1-8 HYPOGONADISM IN ELDERLY MEN—WHAT TO DO UNTIL
THE EVIDENCE COMES
A long-awaited report from the Institute
of Medicine (IOM) concluded that there is insufficient evidence that
testosterone benefits elderly men.
Many studies document that serum
testosterone levels decrease as men age. In contrast to the precipitous and
profound decrease in estradiol concentrations in women at the menopause, the
decrease in testosterone levels in men occurs moderately and gradually over a
period of several decades—from about 600 ng/dL at age 30 to about 400 at age
80. One study reported that about 20%
of men over age 60 had total serum testosterones below the normal range for
young men.
A still unanswered question is whether
this decrease is physiologic (perhaps conveying a benefit) or pathologic
(causing harm).
Another unanswered question is whether
increasing the low-level testosterone in elderly men to the level of younger
men will exacerbate testosterone-dependent diseases such as prostate cancer and
benign prostatic hyperplasia.
2-17 STRUCTURE OF THE 1918 FLU VIRUS
Scientists at the Medical Research Council
(UK) have discovered a crucial structural change in the avian influenza virus
that resulted in the death of 20 million people worldwide in 1918.
The hemaglutanin molecule protrudes from
the surface of the flu virus as a series of spikes. A change in the
configuration of the spikes enabled the avian flu virus to lock on the surface
of human cells. Usually, bird viruses cannot be transmitted to humans. But, in
1918 this subtle change in shape of HA gave the virus the ability to attach to
receptors on human cells as well as bird cells. The virus then spread rapidly
from human to human to infect an estimated billion people—half of the world’s
population at the time.
All of the devastating flu pandemics of
the last century were caused by viruses that came from birds.
Could this happen again? Many believe
so. Eternal vigilance and vaccine
adjustment will hopefully blunt the epidemic.
RTJ
6-13 TACKLING THE NEXT INFLUENZA PANDEMIC
“We must now hasten the preparations for another
inevitable influenza pandemic.”
A recent systemic review concluded that the prophylactic use of neuraminidase
inhibitors (NIs) could lead to a
reduction of 70-90% in risk of symptomatic flu. These drugs have shown efficacy
in preventing transmission of influenza in institutions and community setting.
The availability of a highly effective supplement to vaccination opens to
debate the appropriate role of NIs and other antiviral drugs in the control of
pandemic influenza.
What might be an alternative strategy? It is known that “ring”
vaccination, which has been used in the past, will quell smallpox outbreaks.
The strategy entails post-exposure vaccination of close contacts. For smallpox,
this approach has provided a wide safety net of prevention, while focusing
vaccination where it was needed most. Ring prophylaxis may be applicable to the
initial management of an influenza pandemic. NI treatment of influenza cases
with the infection and prophylactic use for their contacts may decrease attack
rates substantially. It limits usage of the drug to where it is needed most.
Antiviral ring prophylaxis for flu has
proved to be effective in family settings. It requires only short term daily
treatment for a period of 5-10 days, and targets a relatively limited
proportion of the population. Used in this way, NIs may be dispensed more
rapidly and require less of a stockpile.
COST: Tamiflu, 75 mg cost about $6 each capsule—
$60 for a treatment course; $42 for 7-day prophylaxis. I believe most patients
would consider this a bargain.
Healthcare workers should be the first
in line to receive “ring” prophylaxis, and to continue it until assured that
the current vaccine is effective.
Primary care clinicians will likely use
NIs freely to unvaccinated family members during an epidemic of flu. RTJ
LIPID-LOWERING (See STATIN DRUGS)
LIPOSUCTION (See METABOLIC SYNDROME [6-4}; [6-5])
LOW-CARBOHYDRATE DIET (See DIET)
MEMANTINE (See ALZHEIMER’S DISEASE [1-6])
The estimated prevalence of the “metabolic”
(“insulin-resistance”) syndrome is over 20% among adults in the USA.
Middle-aged men with the metabolic syndrome have significantly elevated risk of
all-cause and cardiovascular disease (CVD)
mortality.
It is defined by the National Cholesterol Education Program among persons with 3 or more
of 5 risk factors:
1. BP at or over 130/85
2. Central obesity—waist circumference > 40 inches
in men
3. High triglyceride levels—>150 mg/dL
4. Low HDL-cholesterol— < 40 mg/dL
5. High fasting plasma glucose—at or above 110 mg/dL
After adjustment for age, smoking status, alcohol
consumption, and parental CVD, the relative risks (RR) of all-cause mortality and CVD mortality were higher in men
with the metabolic syndrome who were unfit compared with the fit men. (RR = 2.0
and 2.3)
There was a graded increase in deaths according to
fitness categories. Men in the middle tertile of fitness had 2.0 times the CVD
death rate as those in the upper tertile of fitness Those in the lower tertile of fitness had 3.5 times the risk.
The estimated population-attributable risk for CVD
deaths in males with the metabolic syndrome is 11%. This suggests that about 1 in 10 CVD deaths are directly
attributable to the metabolic syndrome. The public health burden is
considerable.
Low cardio-respiratory fitness was an important risk
factor for premature mortality in men with the metabolic syndrome. Being fit
provides a strong protective effect.
As expected,
physical fitness attenuated risk of death in men without the metabolic syndrome
as well as those with. I omitted this data.
The study is
a reminder of the definition of the metabolic syndrome and its importance as a
health risk. I have to periodically jog my memory about the definition lest I
forget the 5 requirements.
Fitness
also attenuates risks of adverse outcomes in smokers; and in patients with
obesity, coronary disease, hypertension, and diabetes. It is a basic health
measure about which we continue to advise patients, but which they do not often
follow. RTJ
Abdominal obesity (increased abdominal subcutaneous
fat, and increased visceral fat) is
associated with insulin resistance and other risk factors for coronary
heart disease (CHD).
This study asked: Which of these fat deposits is associated
with insulin resistance and increased risk of CHD?
Liposuction in 15 grossly obese women reduced volume
of subcutaneous abdominal fat by 44%. Weight loss = 10 kg; total body fat
decreased by 18%. Liposuction did not significantly alter insulin sensitivity
(assessed by stimulation of glucose uptake in muscle); did not suppress glucose
production by the liver; and did not suppress lipolysis of adipose tissue.
Levels of C-reactive protein and other indicators of
inflammation did not change.
Other risk factors for CHD were unchanged (BP, plasma
glucose, insulin, and lipid concentrations).
Large-volume reduction in subcutaneous abdominal fat
mass did not have any beneficial metabolic effects
despite
a considerable decrease in body weight, waist circumference, and plasma leptin
concentrations.
This provides insight into the mechanism by which
conventional weight loss improves insulin sensitivity.
Induction
of a negative energy balance, not simply a decrease in the mass of fat tissue,
is critical for achieving the metabolic benefits of weight loss. Even small
amounts of weight loss induced by a negative energy balance affect many
variables pertaining to body-fat composition and lipid metabolism—variables
that contribute to metabolic abnormalities associated with obesity.
Conventional weight loss decreases visceral fat mass, intrahepatic fat,
fat-cell size, and the rate of release of fatty acids from intra-abdominal
adipose tissue. Liposuction does not.
Fat loss by conventional obesity treatment decreases
plasma concentrations of C-reactive protein, interleukin-6, and tumor necrosis
factor. It improves insulin sensitivity and inhibits vascular inflammation.
I abstracted
this article mainly to point out the risks associated with intra-abdominal fat
accumulation. Visceral fat drains directly into the portal circulation and into
the liver; subcutaneous fat drains into the general circulation. There is a
vast metabolic difference. RTJ
6-5 THERMODYNAMICS, LIPOSUCTION, AND METABOLISM
Hyperglycemia improves rapidly during caloric restriction. It outpaces the rate of weight
loss. About half of the improvements in glycemic control are achieved during
the first week of a negative energy balance, although the actual fat loss is
typically quite small. Substantial proportions of the early benefits of weight
loss on insulin resistance and hyperglycemia in type 2 diabetes may be
attributed to a negative energy balance.
Similar observations have been made
concerning hypertension. Much of the decrease in BP occurs fairly rapidly in
response to a negative energy balance. There is, however, a return toward
hypertensive levels once weight has reached a plateau.
Visceral adiposity is strongly associated with insulin
resistance. In animals, surgical resection of visceral fat tissue yields marked
and nearly immediate reduction in insulin resistance. The removal of an
equivalent amount of subcutaneous fat has little effect. The relation may be
related, at least in part, to the release of fatty acids into the portal
circulation.
Adipose tissue has endocrine
functions—synthesizing leptin, adiponectin, and cytokines such as tumor
necrosis factor, interleukin-6, and C-reactive protein.
During
World War II type 2 diabetes practically disappeared in the Netherlands. This
was related to the near starvation conditions produced by the invasion by
Germany. RTJ
1-3 “ME TOO” PRODUCTS—FRIEND OR FOE?
Me-too products create competition among
drug and device manufacturers. Competition is a powerful driver for better
quality and lower costs. Health care
leaders who struggle to provide good care with limited resources see me-too
products not as a problem, but as an important part of the solution.
The first product in a new class defines
the baseline value equation. [Value = benefit / harm-cost] The manufacturer may
set a high price and may have no trouble selling the product at its asking
price. When a second product in the same class comes along, its manufacturers
must offer a better value. That product must lead to a better outcome or it
must be less expensive.
For market forces to really work,
physicians have to choose products as if costs matter.
When
should primary care clinicians add a new drug to their practice? Is it a unique and important addition to
therapeutics? Or is it just a “me-too”
drug? It takes several years after entry into general use for all adverse
effects to be known. Ask:
1. Is
the new drug more clinically effective? (Not just “statistically” more
effective.)
2.Is
it as safer or safer than established
drug?
3. Is
it more convenient to administer?. Does it require fewer doses?
4. Is
it less costly?
Primary
care clinicians are often advised not to be the first to prescribe a new drug,
no matter how highly touted, unless it is known to be safe and carry unique and
important benefits
I have
faced (as have most older clinicians) the embarrassment of having a new drug I
had prescribed suddenly withdrawn from the market. The patient will ask for an
explanation. RTJ
More health care professionals are
recognizing the importance of the stories patients tell about their illnesses.
Not only is the diagnosis encoded in the narrative, but also deep and
therapeutic understandings of the persons who bear the symptoms are made
possible through the stories they tell. Only in the telling is the patient’s
suffering made evident.
Narrative competence, defined as the set
of skills required to recognize, absorb, interpret, and be moved by the stories
one hears, is increasingly recognized as a basis for diagnosis and therapy.
Primary
care clinicians bear the greatest opportunity and responsibility for
understanding and responding to patients’ stories. Some writers term this
making a “connexion” with the patient.
It is the
“worried well” and the patient with chronic illness whose narratives should be
developed and understood over time as a basis of therapy and support.
Patiently
listening and understanding narratives will benefit our family members,
children, associates, and friends as well as patients. The art of listening and
responding empathetically is a difficult, life-long quest. RTJ
NATRIURETIC PEPTIDE (See HEART FAILURE [2-5])
1-10 FOLIC ACID AND THE PREVENTION OF NEURAL
TUBE DEFECTS
A public health policy should include both
the mandatory fortification of flour and a recommendation that all women
planning a pregnancy take 5 mg a day.
Each year about a quarter of a million pregnancies result in the birth
of an infant with NTD, or an abortion performed because of such a defect. 85% of them could be prevented if all women
took 5-mg daily before pregnancy and during the first trimester.
A high
percentage of women of childbearing age have unplanned pregnancies. Since the
beginning of pregnancy cannot be predicted in these women, I believe a good
case can be made to recommend all women at risk for pregnancy routinely take FA
daily. Primary care clinicians should take the opportunity to so advise their
younger women patients regardless of the reason for the consultation.
The
benefit/harm-cost ratio of FA is high.
Although overall risk is low, benefit may be great for individuals The
harm is nil. Cost is low. Considering the devastating effect of NTD for the
child and the family, I believe all women at risk of pregnancy should be
informed. RTJ
NICOTINE REPLACEMENT (See SMOKING [2-9])
NONSTEROIDAL ANTI-INFLAMMATORY
DRUGS (NSAIDs )
Non-selective NSAIDs are associated with an increased
risk of heart failure (HF). In susceptible individuals, they raise
systemic vascular resistance and reduce renal perfusion. BP may be elevated,
and edema and HF may result.
The selective COX-2 inhibitors, celecoxib (Celebrex ) and rofecoxib (Vioxx
) are reported to be associated with a
lower risk of gastrointestinal events than the non-selective NSAIDs. Might they also be associated with fewer
cardiovascular and renal complications?
Might celecoxib and rofecoxib differ in their risks?
Relative to non-NSAID users, the rate of admission for
HF was significantly higher for users of rofecoxib (RR = 1.8) and non-selective
NSAIDs (RR = 1.4) , but not celecoxib
(RR = 1.0)
Patients with a history of HF were much more likely to
be admitted for recurrent HF. Those taking celecoxib were more likely to be
readmitted than controls (RR = 1.2), but much less likely than those taking
non-selective NSAIDs (RR = 2.2) and rofecoxib (RR = 1.8)
The authors
state that , in other studies, patients with long-standing hypertension showed
greater increases in systolic BP among those receiving rofecoxib compared with
those receiving celecoxib.
We too often
concentrate on the adverse effects of NSAIDs on the gastrointestinal tract, and
forget those on the cardiovascular and renal systems.
Although
celecoxib may have a slight edge as far as adverse effects are concerned, I
would avoid its use (and that of any NSAID) in patients with a history of HF,
or at risk of HF (including diastolic HF),
as well as patients with uncontrolled
hypertension. RTJ
1-1 TOTAL ENERGY
EXPENDITURE AND PHYSICAL ACTIVITY IN YOUNG SCOTTISH CHILDREN
The epidemic of childhood obesity has been
attributed largely to a decline in total energy expenditure (TEE). This study postulated that the
lifestyle of contemporary young children is sedentary.
Levels of TEE were low at ages 3 and 5 in both sexes. Lifestyles in
this sample of youngsters were sedentary. This would increase risk of obesity.
Their total energy expenditure was significantly lower than the UK estimates
average requirement for energy expenditure for children.
Children typically spent only 20-25 min per day in
moderate to vigorous physical activity. Present recommendations are that they
should accumulate at least 60 min daily. “There is a widespread perception
among parents and health and educational professionals that young children are
spontaneously active. Actually, modern children establish a sedentary lifestyle
at an early age.”
1-2 PHYSICAL ACTIVITY AND OBESITY
The nature of human physiology is such
that it is extremely difficult, if not impossible, to maintain a healthy
bodyweight with a low level of physical activity.
Obesity arises from an imbalance in which energy
intake exceeds energy expenditure. This means that sedentary people must
maintain a low intake of energy to avoid obesity. Human physiology did not
develop to support restriction of energy intake. It is difficult for most
people to do so consistently over time.
We have to teach children (and adults) to use their
intellect to push back against the environment. Such a change can be done by
eating a little less and being a little more physically active than ordinarily.
Small changes would counter the natural tendency to succumb to the
environment.
“We suggest that weight gain in 90% of the
US adult population could be prevented by reducing positive energy balance by
only 100 kcal per day.” Small and achievable changes in behavior can have a big
impact.
Removing
high fructose drinks from ready availability to youngsters is a good first
step. RTJ
Recently, the low-carbohydrate
(“low-carb”; [LC]; Atkin’s) diet has
gained recognition despite modest supportive scientific evidence of
efficacy. A popular version of this
diet recommends extreme restriction of carbohydrate intake to less than 20
grams daily. This level can induce ketosis
and weight loss.
This randomized trial compared the effects
of the LC-ketogenic diet vs a
low-fat, low-cholesterol reduced-calorie diet.
Over 24 weeks, otherwise healthy obese, hyperlipemic
persons who followed a LC diet lost more body weight and fat than those on a
low-fat diet. Triglyceride levels decreased; HDL-cholesterol levels increased.
The LDL-c increased in some subjects. “Because the low-carbohydrate diet may
adversely affect the LDL cholesterol level, it is prudent to monitor the serum
lipid profiles. . . .”
The drop-out rate in persons on the LC diet was lower.
This is important because the value of any diet depends on the degree to which
patients adhere to it over time.
Weight loss in both groups resulted from reduced
energy intake. The method of reducing energy intake differed greatly. The
low-fat, high-carbohydrate diet group received counseling to restrict intake of
fat, cholesterol, and energy. The LC diet group received counseling to restrict
intake of only carbohydrates, not energy. “The voluntary reduction in energy
intake among recipients of the LC diet merits future research.”
Further observation is needed to determine
the long-term (beyond 6 months) effects
of the LC diet. Weight loss may be difficult to maintain
No matter what the diet, weight loss will vary
considerably between individuals. An editorialist suggests that we can
encourage overweight patients to experiment with various methods for weight
control, including the LC diet, as long as they emphasize healthy sources of
fat and protein and incorporate regular physical activity.
“We can no
longer dismiss the very-low-carbohydrate diets. ”
The
determining factor in diet therapy is its effect on long-term (years) weight
control. We wait results of these studies, Thus far, it seems doubtful that
many persons on the LC diet will maintain their weight loss over time.
I believe more studies of the LC diet
will be forthcoming as related to diabetes, coronary disease, hypertension, and
the metabolic syndrome, as well as
obesity. RTJ
6-8 EFFECT OF
LIFESTYLE CHANGES ON ERECTILE DYSFUNCTION IN OBESE MEN
Erectile dysfunction (ED) is common, even in young men. Several modifiable lifestyle
factors are associated with maintenance of erectile function. Men with a body
mass index over 28 have a 30% higher risk of ED. The prevalence of overweight
and obesity in men reporting ED may be as high as 79%, although vascular
factors associated with obesity may play an important role.
This study of obese men with ED determined if a
long-term reduction in BMI and an increase in physical activity would
positively affect erectile functions.
At 2 years an intensive dietary-fitness
program led to over 10% loss of body weight and an increase in physical
fitness. About 1/3 of the men regained erectile function.
For many patients, ED is a manifestation of more
generalized pathology. Hypertension, hyperglycemia, and dyslipidemia are common
co-morbidities. Endothelial dysfunction is likely a pathogenic mechanism common
to these co-morbid states, risk of cardiovascular disease, and ED. The study
demonstrated improvements in endothelial function related to weight loss..
This is not,
however, a practical application. Few patients in primary care practice would
be able to complete such a program.
The main
message is—maintain a healthy lifestyle, don’t wait to repair damage until
after it is done. RTJ
OMEGA 3 FATTY ACIDS (See CARDIOVSCULAR DISEASE [1-5])
4-1 CORTICOSTEROID INJECTIONS FOR OSTEOARTHRITIS
OF THE KNEE
This is the first meta-analysis aimed to
determine the efficacy of intra-articular corticosteroids. Are intra-articular
injections of corticosteroids more efficacious than placebo in improving
symptoms of OA of the knee? How long
does the beneficial effect last?
Six short-term studies showed a significant
improvement. The pooled relative benefit (steroid vs placebo injection) was 1.6 with the number needed to treat to
obtain improvement in one patient = between 1.3 and 3.5. No important harms were reported other than
transient redness and discomfort. Only one of the 6 studies investigated potential
loss of joint space and found no difference between corticosteroid and placebo
up to 2 years.
Two longer-term, high-quality trials
reported a relative benefit of 2.1 with a NNT to benefit one patient in 4.4
over 16 to 24 weeks. One study investigated potential loss of joint space and
found no difference between corticosteroid and placebo up to 2 years. This
study used higher dose triamcinolone (40 mg—equivalent to 50 mg prednisone)
than most other studies and also gave repeated injections (every 3 months for 2
years). No difference in loss of joint space over 2 years. “Currently, no evidence supports the
promotion of disease progression by steroid injections.. Repeat injections seem
to be safe over two years.” This requires confirmation.
Evidence supports short term (up to two
weeks) improvement in symptoms of OA of the knee after corticosteroid
injections. Significant improvement was also shown in the only methodologically
sound studies addressing longer term use. Multiple doses of the equivalent of
50 mg prednisone may be needed to show benefit at 16-24 weeks.
The
data regarding high doses of corticosteroid, repeated periodically, may
encourage some clinicians to increase the dose. I believe many physicians are
reluctant to recommend multiple high-dose injection for fear of further
damaging the joint. The report that high-dose repeated injections over 2 years
did not lead to further damage is interesting and reassuring. This is an
important clinical point which urgently requires confirmation. I believe there is currently concern that
joint damage does occur after repeated injections. If this is not the case,
many patients would benefit from repeated injections of higher dose steroids,
and would welcome a delay in the need
for knee replacement RTJ
Strontium ranelate is an orally active agent recently
re-introduced for treatment of osteoporosis. It consists of two atoms of
strontium and an organic moiety. It acts in a dual manner to stimulate
formation of new bone and decrease bone resorption . SR treatment of postmenopausal osteoporosis led to early and
sustained reductions in risk of vertebral fractures. In a high-risk group of
women with osteoporosis, the NNT to prevent one new vertebral fracture over 3
years = 10
There were no significant differences between groups
in the incidence of serious adverse effects.
Diarrhea was more common in the SR group (6%). Withdrawals were similar. There
was no change in vitamin D metabolites.
“The
current trial establishes the efficacy of strontium ranelate, a familiar
element relaunched as a new compound, in reducing the risk of vertebral
fractures and its role in the armamentarium of therapy for osteoporosis.”
Not
yet ready for prime time. Watch for developments. RTJ
2-6 EXPERTS URGE EARLY INVESTMENT IN BONE
HEALTH
The American Academy of Pediatrics has
issued a policy statement urging physicians to contact schools in their
communities and push for the elimination of sweetened soft drinks. Carbonated
soft drink consumption has increased by 16% since 1970; milk consumption has
decreased by an equal amount. In
addition to displacing milk in the diet, the phosphorus content of soft drinks
may impair absorption of calcium. Milk
is the main source of calcium in the typical American diet. Milk
consumption—and therefore calcium intake—decreases as soft drink consumption
increases.
Much of the focus was on the contribution
of sugary (high fructose) beverages to the obesity crisis.
Prevention
of osteoporosis begins in childhood and adolescence. This is one of the most
important preventive measures primary care clinicians can offer their
patients.
Anyone
living in a retirement home will realize how common and disabling the
kyphotic-osteoporotic spine can become. Development of osteoporosis can largely
be prevented or retarded. I believe it is a major prevention opportunity for
primary care clinicians. Prevention begins in childhood.
Commercial
interests have intruded into our school system in subtle ways. Vending machines dispense not only soft
drinks, but high calorie snacks. Textbooks are not an exception. Advertising
enters them in apparently innocuous ways. TV and radio programs provided for
children in school contain commercial messages. Children can not perceive the
hype. RTJ
3-8 TEN YEAR’S EXPERIENCE WITH ALENDRONATE FOR
OSTEOPOROSIS IN POSTMENOPAUSAL WOMEN
How long is the benefit of bisphosphonates sustained?
This article reports results of a trial of postmenopausal women with
osteoporosis who were treated for 10 years with alendronate (Fosamax).
Bone mineral density (BMD) continued to increase throughout the 10-year period. Lumbar
spine density was increased by doses of 5 mg and 10 mg daily (+ 9% and +14%).
The density of the femoral neck was increased by +3 and + 5%.
Even when alendronate is discontinued, the increased BMD persists
for some time.
The drug was well tolerated over 10 years.
There is some concern that bone may become more brittle as BMD increases due to
prolonged therapy. No evidence, however, of an increase in fracture rate in this study.
The
study reported a
low calcium intake in these women. Deficient intake of calcium and
vitamin D is common in the USA. Providing adequate calcium and vitamin D will
retard development of osteoporosis.
Women (and men) should maintain adequate intake of calcium and vitamin D
throughout their lives. This can usually be attained only by supplementation.
RTJ
5-10 HOMOCYSTEINE LEVELS AND THE RISK OF
OSTEOPOROTIC FRACTURE
Homocystinuria is a rare autosomal
recessive disease characterized by very high plasma homocystine levels. It is also characterized by early onset of
generalized osteoporosis. The underlying pathophysiological mechanism is not
completely understood. It may be
related to a disturbance in collagen cross-linking in bone.
In the general population, a mildly
elevated plasma homocysteine, termed hyper-homocysteinemia, is a common
condition. Hyper-homocysteinemia is recognized as a major risk factor for
atherosclerotic and thrombotic disease, as well as cognitive impairment,
including Alzheimer’s disease.
Are mildly elevated homocysteine levels
related to age-related fractures?
This study determined
homocysteine levels, and followed
over 2400 subjects, all over age 55 (a general, older population) who
participated in two separate prospective studies:
When grouped with regard to sex and age-specific
quartiles, those in the highest quartile had an increase in risk of fracture
twice as high as the risk in the three lower quartiles.
The population-attributable risk of
fracture related to a high homocysteine level was estimated at 19%
A companion study “Homocysteine as a
Predictive Factor for Hip Fracture in Older Persons” comes to the same
conclusion. Compared with the lowest quartile, those in the highest quartile
had a greater risk of hip fracture
(4
times higher in men and 2 times higher in women).
The authors comment that homocysteine
levels are easily modifiable by dietary interventions. The FDA mandate in 1996
led to folic acid fortification of grain products. This has helped reduce the
prevalence of low folate levels (< 7 mmol/L) from 22% to 2% and reduce the
prevalence of homocysteine concentrations higher than 13 mmol/L from 19% to
10%. It remains to be seen if interventions by supplements will reduce rates of
fracture.
Would this
study lead primary care clinicians to more strongly advise a daily multivitamin
supplement?
(In addition to folic acid, supplements contain
vitamin B12 and B6 which are also related to a lowering of homocysteine
levels.)
Decisions
regarding therapy in primary care often do not depend on conclusive evidence of
efficacy. They are also based on reasonable assumptions (accepting that
observational studies may be misleading), and a judgment of the
benefit/harm-cost ratio of the therapy. For daily vitamin supplements, the harm
is nil and the cost minimal. Even if the benefit is very modest, it might be
reasonable to take them. I would advise older patients that a supplement might
reduce risk of fracture and advise them to take a supplement. RTJ
6-7 FREQUENCY OF SYMPTOMS OF OVARIAN CANCER IN
WOMEN PRESENTING TO PRIMARY CARE CLINICS.
Ovarian cancer (OC)
has been called the “silent killer” because symptoms are thought not to develop
until advanced stages when chance of cure is poor. Standard textbooks state
that symptoms do not occur until the disease is advanced. However, several
retrospective studies have indicated that the majority of patients with OC do
have early symptoms, although not necessarily gynecologic in nature.
Identification of early symptoms may have
important clinical implications because the 5-year survival for early stage
disease is 70% to 90% compared with 20% to 30% for advanced-stage disease.
This study compared the frequency,
severity, and duration of symptoms typically associated with OC vs typical symptoms of women attending
primary care clinics.
Women with OC described differences in
symptoms compared with the typical women presenting for care. Symptoms in
patients with OC were more frequent, more severe, and more often had an onset
within 6 months. Patients were much more likely to have a combination of
abdominal bloating, increased abdominal size, and urinary urgency.
These symptoms warrant further diagnostic
intervention because they are more likely to be associated with ovarian tumors.
This
requires the patient to carefully recall and describe her symptoms. And
requires the physician to be especially alert about fully understanding the
onset, severity, and duration of the symptoms. Clarity may be achieved only
after several visits.
Physicians should ask women presenting with
relatively new-onset symptoms specifically about bloating, abdominal size and
urinary symptoms. RTJ
PAIN CONTROL (See CAPSAICIN [4-7])
2-11 COUGHING CAN REDUCE PAIN OF INJECTION
The British
Journal of Plastic Surgery reports
that, when patients cough vigorously as the needle comes into contact with the
skin, the pain of injection is decreased.
There is little doubt that distraction
works. It may be explained by the gate-control theory. Stimuli traveling over
fast nerve fibers partially override painful sensations traveling along slower
nerve fibers.
Coughing may also decrease pain when blood
is being drawn.
PHYSICAL ACTIVITY (See FITNESS)
PLAN B (See EMERGENCY CONTRACEPTION [6-9])
POLYCYTHEMIA VERA (See ASPIRIN [1-14]; [1-15])
PREMENSTRUAL DYSPHORIC DISORDER
2-12 PROZAC
(FLUOXITINE) DROPPED AS INDICATION FOR PREMENSTRUAL DYSPHORIC DISORDER.
Last summer, a European committee reported
that “PMDD is not a well-established disease entity”. It is listed in the DSM
IV only as a research diagnosis. The committee strongly criticized two key
trials of the selective serotonin
reuptake inhibitor fluoxitine (Prozac), noting that in one study almost
half of the participants dropped out, and, in the second study, little attempt
was made to distinguish between mild and severe health problems. There was
concern that women with less severe premenstrual symptoms might receive the
diagnosis and be treated inappropriately.
Some researchers welcomed the decision,
saying that PMDD (which was only recently described) was an invented illness—a
strong example of the medicalization of ordinary life.
Prozac
was first approved for PMDD in 2000 by the FDA. An aggressive promotional
campaign followed.
This leaves
us with PMS (“premenstrual syndrome”).
PMS can be severe and accompanied by depression.
A variety of lifestyle changes and drugs, including
hormonal therapy, have been suggested.
I believe
many MDs will continue to prescribe selective serotonin reuptake inhibitors
(including
Prozac ) off label at low dose (20 mg as a trial
therapy for select patients). PMS can
be disabling. There are few effective alternative therapies. RTJ
5-6 PREVALENCE OF PROSTATE CANCER AMONG MEN
WITH A PROSTATE-SPECIFIC
ANTIGEN <
4.0 NG PER MILLILITER
This study investigated the prevalence of prostate
cancer (PC) among 3000 men (baseline
age 62 to 91) whose PSA consistently remained at 4.0 or less over 7 years. A
prostate biopsy was performed at year 7.
Overall prevalence of PC was a mean of 15%, increasing
linearly from 6.6% to 26.9%
Overall prevalence of high-grade PC was a mean of
2.2%, increasing linearly from 1% to
6.7%
The positive predictive value of a PSA less than 4.0 has not been well
defined. Previous large studies suggested for men over age 50, a value of 4.0
should be used as the upper limit of the normal range. Another study among men
with a PSA 2.6 to 4.0 reported that detection of clinically important PC was
the same as that among men with PSA over 4.0
It is not surprising that the predictive value of PSA levels is not
known.
“There is no PSA value below which a man can be
assured that he has no risk of prostate cancer.” This is despite the impression
of many clinicians that men with a level under 4.0 ( 92% of all men) have
almost no risk of PC.
“Although the
use of PSA testing in the United States has led to earlier diagnosis and a
marked shift in the stage at which prostate cancer is identified, it is unclear
whether PSA testing reduces the rate of death from prostate cancer.”
The uncertain benefits of PSA screening have resulted
in different recommendations from policymaking organizations. The large
difference between a man’s risk of death from PC (3% to 4%) and his lifetime
risk of the diagnosis of PC (17%) suggests that many PCs detected in routine
practice may be clinically unimportant. Lowering the PSA threshold for
proceeding to biopsy would increase the risks of overdiagnosis and overtreating
clinically unimportant disease.
In this
study, the prevalence of PC in
asymptomatic men with a PSA level consistently 4.0 and below, ranged from 66 per 1000 men to 269 per 1000
men, depending on level of PSA. And the risk of high-grade PC ranged from about 10 per 1000 men to 67 per
1000 men. Prevalence must be much greater still in men with PSA above 4. This
must be the highest prevalence of any asymptomatic cancer, by far.
Progression
to clinical disease must be low, since only up to 3% of men die of PC.
Obviously
the disease is grossly overdiagnosed and overtreated.
Considering
that 92% of men tested have a PSA of 4.0 or less, and that the prevalence of PC
in this group varies up to 27%, does it
not follow that the great majority of prostate cancers occur in men with a PSA
4.0 or less?
This study, I
believe, will encourage primary care clinicians to be more circumspect in
recommending routine PSA screening RTJ
5-7 PROSTATE CANCERS IN MEN WITH LOW PSA
LEVELS—Must We Find Them?
There is disagreement as to what level of PSA should
prompt a biopsy. Controversy stems from a dilemma: 1) Use of higher PSA thresholds risks may miss an important
cancer until it is too late. 2) Use of
lower PSA thresholds increases the number of biopsies and the proportion of
biopsies that identify clinically insignificant disease.
It should not
be surprising that 10% to 27% of patients age 62 to 91with a PSA of 4.0 or less
were found to have PC. Ninety percent of men age over 50 have PSA values 4.0 or
less. Thus, quite a few of these men harbor PC. “Although it would be desirable to detect high-grade cancers that
are likely to be life threatening in men with PSA below 4.0, the identification
of such cancers will require the development of new biomarkers.”
The commentator suggests that we should maintain a
cutoff point of 4.0 and above for older men, and 2.5 be used for men age 40-50.
Men with baseline PSA 1.0 to 4.0 are at significantly higher risk for a
diagnosis of PC over the next 10 years than are men whose baseline PSA is below
1.0. Thus, in these men, it makes sense to track the rate of rise in PSA
values. This has been shown to correlate directly with the risk of cancer.
The cutoff value of PSA that results in 95%
sensitivity (detection of 95 % of the cancers) is close to 4.0 for men between
ages 50 to 70. The cutoff value of PSA that results in 95% sensitivity for men
age 40 to 50 is close to 2.5 Because most of the variability in PSA levels is
due to benign prostate enlargement that occurs with age, and men below age 50
are unlikely to have such enlargement, a threshold of 2.5 seems reasonable for
these men..
With a PSA in the range of 2.6 to 6.0, younger men are
more likely to have curable PC—driven by the fact that younger men are more
likely to have less aggressive cancers.
The evidence suggests that the detection of PC at younger ages would have a
greater effect on the likelihood of remaining free from disease after treatment
than would the detection of PC in older men.
Considering the lifetime risk of death from PC is 3%,
and the lifetime risk of a diagnosis of PC is 16%, it is apparent that any
approach that finds more cancers without quantifying the clinical significance
of the detected disease will increase overdiagnosis and overtreatment. This,
together with the absence of proof that PSA screening saves lives, suggests
that physicians should be circumspect about routinely recommending a prostate
biopsy for men over age 50 who have a PSA level 4.0 or less.
Men who
present for periodic health examinations should be made aware about the
availability of the PSA test. They should be informed (about risks as well as
benefits) so they can make an informed decision about the need for routine
screening. The enthusiasm for screening in general in the USA suggests that
most men will decide to be tested.
If up to one
fourth of all men over age 62 with a PSA of 4.0 or less have PC, and about 90%
of men have PSA below 4.0, it follows that the vast majority of PCs exists in
men with a “low” PSA.
Few screening procedures have been more
controversial. Undoubtedly screening with PSA has led to extension of life
length in some men. I believe it has led to more unnecessary procedures and
adverse complications, and has imposed
great long-lasting anxiety.
The
controversy continues. I believe it more prudent to screen men under age 60
than those above 60. As patients attain greater age, enthusiasm for screening
should wane. RTJ
6-3 NATURAL HISTORY OF EARLY, LOCALIZED PROSTATE
CANCER
Even without any initial treatment, only a small
proportion of patients diagnosed with PC at an early stage die of the disease
within 10 to 15 years following diagnosis.
This observational study of the long-term natural
history of localized PC (diagnosed at a mean age 72) assessed disease
progression and mortality over years of watchful waiting.
Over 21 years, most patients died of causes other than
PC. Only 9% of the cohort survived.
Poor differentiation (in only 4% of the cohort) was a
strong predictor of cancer-specific death. This became evident within the first
5 years.
Further follow-up after
15 years revealed a substantial worsening of the cancer. The cause-specific mortality from PC
increased by 3-fold during years 15 to 20 after diagnosis. .
“If our data reflect a real phenomenon, they would
imply that the probability of progression from localized
and
indolent to metastatic and mortal disease increases markedly after long-term
follow-up.”
This would support radical treatment, notably among
patients with an estimated life-expectancy of over 15 years.
This would
argue for greater screening of younger men; less aggressive screening in older
men. Long term follow-up may be necessary to observe the full benefits of early
diagnosis and definitive treatment in younger men. Older men likely die of
other causes.
According to
these data, even if your PC is highly differentiated, you still run a risk of
about 2 in 100 of developing metastatic disease each year, and about 1 to 2
chances in 100 of dying of PC each year. If you survive over 15 years, these
chances are increased by 300%.
Prostate
cancer is never cured spontaneously.
If you live
long enough and are not treated, your chance of developing metastatic disease
(requiring orchiectomy or estrogen therapy) and fatal PC is high, even if you
have a highly differentiated PC. If you have a poorly differentiated grade PC
and are not treated, you will likely die of it within 5 years.
No doubt some
lives are saved by radical treatment. Who to treat and when to treat remains a
dilemma. RTJ
PROSTATE SPECIFIC ANTIGEN (See PROSTATE CANCER)
PROVIGIL (See WAKEFULNESS [1-16])
3- 12 TAMSULOSIN
(FLOMAX) IS EFFECTIVE FOR RENAL COLIC
In patients with renal colic due to
juxtavesical stone, tamsulosin (Flomax) 0.4 mg given 3 times daily was
associated with greater chance of passing the stone. And fewer hours to
expulsion, fewer number of injections of diclofenac, lower hospitalization
rate, and reduced need for endoscopic stone removal.
A therapeutic
measure worth keeping in mind.
The major
adverse effect of Flomax is postural hypotension. The PDR suggests the highest
dose should be 0.8 mg daily. A daily dose of 1.2 mg (0.4 mg 3 times daily) will
likely be associated with greater likelihood of hypotension. RTJ
SLEEP (See WAKEFULNESS [1-16])
SMOKING and SMOKING
CESSATION
“If it were
not for the nicotine in tobacco, people would be little more inclined to smoke
than they are to blow bubbles.”
Experimenting with smoking usually begins
in the early teenage years. It is driven predominantly by psychosocial motives.
Smoking a cigarette is a symbolic act of rebellion, and a statement of
independence. The desired image is
sufficient for the novice smoker to tolerate the aversion of the first few
cigarettes, after which the pharmacological factors assume much greater
importance. As the force from the psychological symbolism subsides, the
pharmacological effect takes over to sustain the habit. Absorption of nicotine
from the lung and transfer to the brain is almost instantaneous and complete.
Tolerance soon develops, and chronic users probably do not obtain
absolute improvements in performance, cognitive processing, or mood. A
plausible explanation for why smokers perceive cigarettes to be calming may
come from a consideration of the effects of nicotine withdrawal. Smokers start
to experience impairment of mood and performance within hours of their last
cigarette, and certainly overnight. These effects are completely alleviated by
smoking a cigarette.
“Early cessation is especially important.”
2-7 ASSESSMENT OF
DEPENDENCE AND MOTIVATION TO STOP SMOKING
Whether a smoker succeeds in stopping
smoking depends on the balance between: 1) motivation to stop, and 2) degree of
dependence. Clinicians must be able to assess both of these characteristics.
Motivation is important because “treatments” to assist with smoking cessation
will not work unless the smoker is highly motivated. Dependence is especially
important in smokers who do not wish to stop. The degree of dependence
influences the choice of intervention.
The practical objective of assessing motivation is to identify smokers
who are ready to make a quit attempt. The
main value of measuring dependence is to judge the need for pharmacotherapy.
Motivation to stop can be assessed by simple direct questions about the
interest in stopping and intention to quit. However, the degree of motivation
seems to play a small role in success; once a quit attempt is made, markers of
dependence are far stronger determinants of success.
I believe primary care clinicians should
frequently assess smoker’s motivation to quit. If the patient expresses no
interest in stopping there is no benefit in pursuing the subject. Raise the
question again at a later consultation. Don’t give up.
Smokers who
develop angina, have an MI, or stroke, or other serious illness are more likely
to quit. This is a great opportunity. It is amazing, however, how many relapse
after a time. RTJ
2-8 USE OF SIMPLE ADVICE AND BEHAVIORAL SUPPORT
The most effective method of helping
smokers quit is to combine drug therapy (nicotine or buproprion [Zyban] ), with advice and behavioral support.
Simple
advice: “The best thing you can do for your health is to stop smoking. I
would advise you to stop as soon as possible.”
The success rate of brief advice, however, is modest, achieving
cessation in about 1 in 40. Nevertheless, it is one of the most cost effective
interventions in medicine because the cost is so low. It takes only 1 to 2
minutes in routine consultations.
Behavioral
support: Intensive behavioral support is provided outside routine clinical
care by trained counselors. About 1 in 13 smokers who are motivated enough to
attend counseling sessions are likely to quit. No one type of intensive
behavioral support is clearly more effective than any other.
The most effective interventions combine
behavioral support with drug treatment.
Primary
care clinicians are already aware of the great benefits of quitting smoking.
Yet, I believe few routinely ask about smoking and fewer still attempt to offer
help. They then miss “The greatest opportunity to improve their patient’s
health”
We should
persist. Don’t be discouraged by the poor success rate. I believe obtaining one
success in cessation is a benefit equivalent to one coronary by-pass. RTJ
2-9 NICOTINE REPLACEMENT THERAPY
Nicotine products are available to all smokers who
want to stop smoking. The purpose is to blunt withdrawal symptoms. Nicotine
replacement therapy (NRT) is most
effective when used in conjunction with behavioral and other types of
non-pharmacological-cessation interventions.
NRT makes cigarettes less rewarding. It
does not completely eliminate symptoms of withdrawal, possibly because none of
the available delivery systems reproduce the rapid and high levels of nicotine
in the brain achieved by inhaling cigarette smoke.
The most recent Cochrane review data
suggest that NRT doubles achievement of cessation.
NRT should be offered to any regular
cigarette smoker who is prepared to make a quit attempt.
It is less harmful than continued smoking
even in pregnancy and cardiovascular disease. Increased efforts to quit should
be made in these patients,
2-10 BUPROPION AND OTHER NON-NICOTINE PHARMACOTHERAPIES
Bupropion is as effective as nicotine
replacement when given in association with intensive behavioral support,
achieving a 19% long-term abstinence. It also seems to attenuate the weight
gain associated with cessation of nicotine. Use beyond the recommended 8 weeks
may confer further protection against relapse.
One study suggested that combined bupropion-nicotine
patch produces higher quit rates.
Nicotine replacement is still the
treatment of first choice.
Age-related macular degeneration (MD) is related to smoking.
Three cross-sectional studies of over 12
000 patients reported that current smoking leads to a 3- to 4-fold incidence of
MD compared with non-smokers. Indeed, the relative risk of smoking associated
with MD is higher than the relative risk with ischemic heart disease. A
dose-response relationship has been established.
Observational studies show a protective
effect of smoking cessation on development of MD.
I was unaware of this association.
Informing patients may be a powerful incentive to quit. RTJ
4-8 ABC OF SMOKING CESSATION: HARM REDUCTION
Smoking is primarily a nicotine-seeking behavior.
For individuals addicted to nicotine,
cutting down, switching to “low tar” cigarettes, and switching to pipe or
cigars do not reduce risk.
There is good evidence that use of
smokeless tobacco is less risky than cigarettes.
The technology to develop safe, inhaled forms of nicotine that could
provide a more satisfactory alternative to cigarettes is available. In the
current regulatory framework, such products would not be licensed and therefore
are not commercially available. “This imbalance in the regulation of nicotine
needs to be redressed urgently in favor of public health.”
Should
primary care clinicians advocate their patients who are recalcitrant smokers to
judiciously use nicotine replacement in conjunction with cigarette
smoking? My PDR (specifically for
Nicotrol inhaler) states that patients should be urged to stop smoking
completely while using this product. Adverse effects may occur due to high peak
nicotine levels. I believe this statement by the drug manufacturer is primarily
a defense against litigation.
Should we
advise switching to snuff?
Would it be
reasonable to encourage manufacture of very high-content nicotine cigarettes?
This could easily be done.
These approaches open legal difficulties. We
are still constrained by outside forces from applying the best medical care
possible. RTJ
Is there any benefit in lowering LDL-cholesterol below
the recommended 100 mg/dL?
This study, in patients with established
coronary atherosclerosis, compared the effect of moderate lipid-lowering by 40 mg pravastatin (Pravachol) with intensive
lowering by 80 mg atorvastatin (Lipitor). Final mean LDL-c was 110 in the Pravachol group and 79 in the Lipitor
group.
The main outcome (progression of coronary
atherosclerosis as determined by intracoronary ultrasound) favored
atorvastatin. Over 18 months, the atherosclerotic burden in the Pravachol group increased by +2.7%
compared with – 0.4% in the atorvastatin group.
“These findings have considerable
implications for treatment guidelines for patients with dyslipidemia and
established CAD.”
Note
this was a study of lipid-lowering and atherosclerotic progression in patients
with established CHD (a high risk group). It did not report any clinical
benefits..
The larger
problem of primary prevention is unanswered.
The
benefit/harm-cost ratio of intensive statin therapy is not known.
We are becoming
a nation of statin takers. Should the recommended dose be the highest
demonstrated to produce surrogate end-point benefits? Should primary care
clinicians now recommend 80 mg of atorvastatin for all? I believe not. The excess cost would be
considerable. And, despite the report that the drug “was well tolerated”, there
will be serious adverse effects.
Note that
LDL-c reached a level below 100 mg/dL in 65% of the group receiving 40 mg
Pravachol. I believe it reasonable to start with a moderate dose and gradually
increase if needed.
In a large group of patients at high risk of vascular disese, statin
therapy rapidly reduced risk of ischemic stroke with no apparent increase in
risk of hemorrhagic stroke. Benefits occurred
even among those who did not
have high cholesterol concentrations. Statin therapy also reduced the risk of
major vascular events among people who had previously experienced a stroke or
other cerebrovascular event.
A reduction in LDL-cholesterol from about
154 mg/dL to about 115 mg/dL reduced risk of stroke and other major vascular
events by about one-quarter. Lowering it from about 115 mg/dL to about 77 mg/dL
also reduced risk by about one quarter.
“Current guidelines could, therefore, lead to substantial undertreatment
of high-risk patients who present below, or close to, particular targets for LDL
reduction.”
“These results have important implications
for revising treatment guidelines which do not currently take into account
cerebrovascular disease risk reduction when considering the initiation of
statin therapy.”
“Statin therapy should now be considered routinely for all
patients at high risk of stroke, irrespective of their initial cholesterol
concentrations. “
This
study confirms the widely-held belief that statin therapy reduces risk of
stroke as well as coronary disease. It also strengthens the observation that
lowering LDL-cholesterol below levels usually considered “satisfactory” will further reduce risk of atherosclerotic
disease.
The risk of
events associated with cardiovascular
risk factors increases linearly. There are no artificial cut-points dividing “satisfactory” levels vs
“unsatisfactory” levels. RTJ
4-2 PHARMACOLOGIC LIPID-LOWERING THERAPY IN
TYPE 2 DIABETES
Most adverse outcomes from diabetes are
due to vascular complications, either micro-vascular or macro-vascular.
Macro-vascular complications are more common and severe. Up to 80% of patients
with type 2 diabetes (DM2) will develop or die of
macrovascular disease. Associated costs are 10 times greater than for
microvascular complications.
The foremost goal of therapy in type 2
diabetes should be prevention of cardiovascular disease through optimization of
risk factors. This includes aggressive treatment of hypertension,
lipid-controlling therapy, smoking cessation, and use of daily aspirin.
Current evidence suggests that lipid
control leads to about a 25% reduction in major cardiovascular events.
For primary prevention (statins vs no
statin in patients without established cardiovascular disease) the NNT over 4
years to prevent one cardiovascular event = 35; for secondary prevention the
NNT = 14 to prevent one event over 5 years.
“Given the absolute risk reductions
observed, treatment will probably be cost-effective under most
circumstances.” This simplifies and
reduces the cost of treatment and would be similar, for example, to simply
prescribing a daily aspirin for a patient with diabetes.”
This study
presents a simplifying common- sense clinical approach. for primary care. We
need more guidelines like this. It comes close to advising statins for all
patients with DM2 RTJ
4-3 INTENSIVE VERSUS MODERATE LIPID LOWERING
WITH STATINS AFTER ACUTE CORONARY SYNDROMES
Enrolled over 4000 patients (mean age 58)
who had been hospitalized for an acute coronary syndrome (ACS) within the
preceding 10 days. ACS defined as acute myocardial infarction (with or without
ECG evidence of ST-elevation), or
high risk unstable angina.
Randomized to: 1) moderate-intensity
treatment with 40 mg pravastatin ( Pravachol
), or 2) high-intensity treatment with
80 mg atorvastatin (Lipitor) daily.
Mean achieved LDL-cholesterol was 95 mg/dL
in the pravastatin group and 62 in the atorvastatin group.
Over 2 years, the more intensive regimen
with atorvastatin resulted in a lower risk of death and major cardiovascular
events as compared with the moderate pravastatin regimen. The NNT for 2 years
to prevent one death, myocardial infarction, angina requiring
rehospitalization, revascularization, or stroke = 53
“Although prior placebo-controlled studies
have shown that a standard-dose statin is beneficial, we demonstrated that more
intensive lipid-lowering significantly increases this clinical benefit.”
Although both drugs were “generally well
tolerated”, there were significantly more liver-related side effects with
high-dose atorvastatin. About 1/3 of all patients in both groups dropped out
over the 2 years.
“Our results suggest that after an acute
coronary syndrome, the target LDL-cholesterol level may be lower than that
recommended in the current guidelines.”
This
was a secondary prevention trial in a very high risk group. Benefits would be
considerably less if high-dose atorvastatin were used in primary prevention.
Certainly, these results cannot be extrapolated to primary prevention.
The authors
suggest that the high-dose regimen “significantly” increased clinical benefit.
Primary care clinicians must ask—is this “clinical” benefit applicable to every
day practice? Patients with an acute
coronary syndrome and their doctors must decide if one chance in 53 over 2
years is worth while, Note that harms (liver disturbance) were statistically
significant, and, I believe, as clinically significant as the reported benefits
in the high-dose patients. Cost, adverse effects, and likelihood of
discontinuation of treatment must be considered. Some patients, knowing they are at very high risk of death or recurrence, would be inclined to
accept the high-dose.
The high drop-out rate because of an adverse
event, or the patient’s preference, or “other reasons” is disturbing. This occurred despite patients’ knowledge
that they were at high risk of recurrence and death. Drop-outs would likely be
higher still in primary care practice.
Pravastatin
has the advantage of not being significantly metabolized by the P450 system in
the liver.
Thus, concerns about interactions between pravastatin
and concomitantly administered drugs is much less than with atorvastatin, which
is metabolized by the P450 system. RTJ
5-5 LIPID-LOWERING THERAPY AND IN-HOSPITAL
MORTALITY FOLLOWING MAJOR NON-CARDIAC SURGERY
Lipid-lowering therapy inhibits
development of atherosclerotic plaques. It is anti-inflammatory and can improve
endothelial function and produce a stabilizing effect on vulnerable plaques.
These properties may be especially beneficial in the perioperative period
because the disruption of unstable plaques is believed to be responsible for
most cases of perioperative MI.
This retrospective cohort study was based
on hospital and pharmacy records of over 790 000 patients who underwent major
non-cardiac surgery at one of 329 hospitals in the USA.
Lipid-lowering therapy in the first 2 days
was associated with a lower mortality:
2.18% of the lipid lowering group died compared with 3.15% of those who
did not receive it, or for whom treatment was delayed beyond the first 2 days. The number needed to
treat to prevent one death ranged from 30 in patients at high risk of
cardiovascular disease to 186 for those at low risk.
What
a remarkable effort! A noble attempt,
subject to bias and confounding. A
provocative study, not definitive—more hypothesis-generating than conclusive.
I suspect
that most patients who used statins in the first 2 days were using statins
before admission to the hospital for the surgery.
The study
used a statistical device termed “propensity matching” to analyze effects of
statin use vs no--statin use. I do not fully understand propensity
matching. It is an attempt to
subclassify participants into groups with common attributes. And to determine
risk differences within the groups as one would do in a case-control study.
So. . .
would you take a statin before undergoing an elective major surgery? Note that patients at the highest
cardiovascular risk gained the most benefit. The majority of older persons in
the USA have an indication for statin therapy. This being the case, should not
many patients facing elective surgery take a statin beforehand? I believe I would. RTJ
6-1 ASSOCIATION OF STATIN THERAPY WITH OUTCOMES
OF ACUTE CORONARY SYNDROMES: The GRACE
Study
Statin drugs may have effects in addition
to their effect on lipids. These include modulation of inflammation, inhibition
of platelet function and thrombosis, and enhancement of endothelial function.
The ability of statins to immediately
affect basic pathophysiologic mechanisms has increased interest in their
potential role in acute coronary syndromes. (ACS)
This study examined the association
between previous and early in-hospital statin therapy and outcomes of ACS.
Patients who presented with an ACS who
were already taking statins were less likely to present with ST-segment
elevation MI, experience a large infarct, and have important clinical
complications, or die.
Much of the observed effect was lost if
statin therapy was not continued during hospitalization. Such patients
had
death rates similar to patients who had never received statins. Withdrawal of
statins reduced the protective effect of statin pretreatment.
In statin-naďve patients, early statin
therapy was associated with an improvement in outcomes.
Should primary care clinicians act on these
conclusions? Primary care clinicians
often act on inconclusive evidence if the putative benefit/harm-cost ratio of
the intervention is high. Although the outcomes of the study require
confirmation and further experience, I believe the benefit/harm-cost ratio of
immediate statin therapy (as of immediate aspirin therapy) for patients with
ACS is potentially high. The benefit is potentially life-saving.
The harm
and cost of short-term therapy is very low. I
would give a high-dose statin immediately on presentation of a patient with presumed ACS.
Those on
statins long-term should be continued on statins when admitted for ACS. Those
not on statins should start them immediately. And, of course, continue after discharge.
A study “Lipid-Lowering Therapy And
In-Hospital Mortality Following Major Non-Cardiac Surgery” (See Practical Pointers May 2004 ) also
presents evidence of immediate protective effects of statins given within the
first 2 days after major surgery. RTJ
6-14 DANGERS OF ROSUVASTATIN (Crestor) IDENTIFIED BEFORE AND AFTER FDA
APPROVAL
A letter to the editor from Sidney M Wolfe, Public Citizen’s
Health Research Group, Washington DC. Lancet June 26, 2004; 363: 2189-90
comments:
The lipid-lowering drug rosuvastatin (Crestor; Astra-Zeneca) is currently in
the midst of the most heavily financed launch of a prescription drug ever.
The correspondent presents available
pre–marketing and post-marketing evidence of the adverse effects of the drug.
Pre-marketing:
Documents included a acknowledgement of a
risk of severe myopathy and rhabdomyolyis which clearly increased at the
highest dose (80 mg). The preapproval document also stated that 80 mg is
associated with a high frequency of creatine kinase elevations (CK 10 times
upper normal). Crestor was approved
with the belief that lower doses would be much safer. The 80 mg dose was
subsequently discontinued.
Post-marketing:
Myopathy:
Since marketing of rosuvastatin, there have been 18 additional cases of
rhabdomyolyis. Two patients were using 40 mg; five using 20 mg; 11 using 10 mg.
Renal toxicity: Rosuvastatin is associated with renal abnormalities.
A small percentage exposed primarily
to 80 mg had increased frequency of persistent proteinuria and hematuria, and,
in some patients, an increase in serum creatinine. There is a reported
dose-associated risk.. The 10, 20, and 40 mg doses have been associated with increasing risk up to 1% of
patients. In individuals who develop ++ proteinuria or more, the percentage
with an increase of creatinine of over 30% rose incrementally with dose—from
14% in the 5 mg daily dose to 33% in the 40 mg dose.
There have been 8 reported cases of
acute renal failure and 4 of renal insufficiency since marketing began. Nine
were using 10 mg. .
Other “currently approved statins do
not have similar renal effects”.
“By now, the number of reported
cases of rhabdomyolyis and renal insufficiency or renal failure—20 of which
have occurred in people using 10 mg—is certain to have increased substantially
from the number filed by April 13, 2004.”
Efficacy:
A statistical review of comparative
efficacy found no significant difference in LDL-cholesterol lowering between 5,
10, and 20 mg of rosuvastatin and 20, 40 and 80 mg of atorvastatin.
“The renal toxicity, high rate of cases of
rhabdomyolyis compared with other statins, and lack of unique benefits are
compelling reasons to remove rosuvastatin from the market before additional
patients
are
injured or killed.” The correspondent
recalls that cerivastatin (Baycol)
was removed from the market because of increased risk of myopathy.
==========
A
letter to the editor July 10, 2004; 364: 135 from Gunnar O Olsson,
Astra-Zeneca, Molindal, Sweden offers a rebuttal:
Crestor
has a safety profile comparable to those of other marketed statins. (The US FDA
has reviewed post-marketing safety data and has supported this conclusion.)
Crestor
was the most extensively studied statin ever submitted for regulatory review.
More than 60 countries have approved it on the basis of an excellent
benefit/risk profile. “More than 80% of patients can reach their LDL
cholesterol goal on the usual start dose of 10 mg.”
The reported rate of rhabdomyolyis has
remained very low (< 1 in 10 000) is consistent with the rates of all
currently marketed statins.
Proteinuria has been associated with Crestor, but is transient, and often
resolves on continued treatment. It is not predictive of acute or progressive
renal disease.
Astra-Zeneca is surprised that The Lancet
published a letter containing inappropriate comparisons that serve to cause
undue alarm. “The letter, which is a rehash of misinformation presented by
Public Citizen in the past includes reference to a non-marketed dose (80 mg)
and is “highly speculative”.
“Rosuvastatin has an excellent
benefit-risk profile compared with other marketed statins, having a better
efficacy lowering LDL cholesterol and raising HDL cholesterol and a safety
profile comparable to those of other marketed statins.”
Comment:
These
letters raise an important clinical point. When should primary care clinicians
add a new drug to their practice?
Is Crestor
a unique and important addition to therapeutics? Or is it just a “me-too” drug? Should primary care clinicians
prescribe it a the present time?
1.
Is Crestor more effective in lowering LDL?
No. Other statins lower LDL just as much, although they might require a
higher dose. Remember, this is a laboratory endpoint, not a clinical
endpoint. Clinical efficacy has not
been established.
2.
Is Crestor as safe as other statins?
This is the dispute. That the 80 mg dose has been withdrawn because of
toxicity raises caution. It will take several years of general use in the USA
for the FDA to determine toxicity. Certainly, Crestor is not safer.
3.
Is Crestor more convenient to administer. Does it require fewer doses? No
4. Is Crestor
less costly? No. Costs are comparable.
The first
letter may raise an entirely unwarranted red flag. I do not know. I abstracted these letters mainly to
reinforce the long-honored and oft-repeated admonishment to primary care
clinicians not to be the first to prescribe a new drug, no matter how highly
touted, unless it is known to be safe and carry unique and important benefits.
Regardless of the question of toxicity, I do not believe the benefits of
Crestor are unique or comparatively important.
I would not
prescribe Crestor at this time. If it proves equally or less toxic, maintains
its reported comparative efficacy in reducing LDL-c, and has a significant cost
benefit, I would consider prescribing it.
I have
faced (as have most older clinicians) the embarrassment of having a new drug I
had prescribed suddenly withdrawn from the market. The patient will ask for an
explanation. RTJ
2-2 POPULATION-BASED STUDY OF EARLY RISK OF
STROKE AFTER TRANSIENT ISCHAEMIC ATTACK OR MINOR STROKE.
Ischemic strokes are frequently preceded
by a transient ischemic attacks (TIA). This warning gives an
opportunity to prevent stroke. This study determined frequency of stroke
following a TIA of minor stroke.
7 days 1
month 3 months
Stroke after a TIA
(%) 8 12 17
Recurrent stroke after minor stroke. (%) 12 15 19
“For stroke prevention to be most
effective, patients will need to be seen within the first few hours or days.”
Many
of these patients had risk factors for stroke at baseline (previous TIA,
hypertension, smoking, diabetes, angina, previous myocardial infarction, and
hyperlipidemia).
They were a
high risk group. Interventions (primary prevention) prior to the incident TIA
or minor stroke would have lowered the risk considerably. RTJ
2-3 SECONDARY PREVENTION FOR STROKE AND
TRANSIENT ISCHAEMIC ATTACKS
Epidemiologic studies show no demonstrable
floor exists for the relationship between BP and risk of stroke. Risk continues
to halve for every 10 mm Hg fall in diastolic even if initial BP is within
conventionally normal limits.
“Definitions of hypertension and
hypercholesterolemia in any patient with stroke or TIA seem artificial.” Irrespective of starting levels, almost all
patients may benefit from reduction of BP and cholesterol.
A general therapeutic principle is emerging. There is no cut-point
below which risk is eliminated. Try to reduce BP, LDL-cholesterol, HbA1c, body
mass index, abdominal girth and other risk markers to as low a level as
reasonable without encountering adverse effects. The cut-point for smoking is
an exception. There is only one cut-point—cessation. RTJ
In a large group of patients at high risk of vascular disese, statin
therapy rapidly reduced risk of ischemic stroke with no apparent increase in
risk of hemorrhagic stroke. Benefits occurred
even among those who did not
have high cholesterol concentrations. Statin therapy also reduced the risk of
major vascular events among people who had previously experienced a stroke or
other cerebrovascular event.
A reduction in LDL-cholesterol from about
154 mg/dL to about 115 mg/dL reduced risk of stroke and other major vascular
events by about one-quarter. Lowering it from about 115 mg/dL to about 77 mg/dL
also reduced risk by about one quarter.
“Current guidelines could, therefore, lead to substantial undertreatment
of high-risk patients who present below, or close to, particular targets for LDL
reduction.”
“These results have important implications
for revising treatment guidelines which do not currently take into account
cerebrovascular disease risk reduction when considering the initiation of
statin therapy.”
“Statin therapy should now be considered routinely for all
patients at high risk of stroke, irrespective of their initial cholesterol
concentrations. “
This
study confirms the widely-held belief that statin therapy reduces risk of
stroke as well as coronary disease. It also strengthens the observation that
lowering LDL-cholesterol below levels usually considered “satisfactory” will further reduce risk of atherosclerotic
disease.
The risk of
events associated with cardiovascular
risk factors increases linearly. There are no artificial cut-points dividing “satisfactory” levels vs
“unsatisfactory” levels. RTJ
5-11 PREVENTION OF DISABLING AND FATAL STROKES
BY SUCCESSFUL CAROTID ENDARTERECTOMY IN PATIENTS WITHOUT RECENT NEUROLOGICAL
SYMPTOMS. Patients with
substantial ( 60-99%) carotid narrowing are at increased risk of stroke. Risk
is greater if they are already symptomatic (ie, have recently suffered some
relevant neurological symptoms).
Carotid
endarterectomy (CEA) can remove
arterial narrowing. The surgical procedure involves risk of perioperative
stroke and death. Moreover, even successful CEA might not permanently eliminate
all thromboembolic risk. The balance of risk and long-term benefit is
uncertain.
What is the benefit/risk ratio of CEA for asymptomatic patients?
Because of the immediate risk of stroke or
perioperative death, benefits for CEA did not outweigh that of watchful waiting
until after 2 years.
Among patients up to 75 years of age with severe
carotid stenosis but no relevant neurological symptoms, CEA reduced incidence
of stroke or death over 5 years by about 6%.
(This takes into account the 3% perioperative hazard of death or
stroke.)
Combining the perioperative events and the
non-perioperative strokes, the net 5-year risks were 6.4% vs 11.8%. (Absolute difference = 5.4%; NNT = 18). For fatal strokes 2.1% vs 4.2% (NNT = 48).
Benefits will exceed risks only if perioperative
hazards remain low. Surgical expertise may indeed be improving, but so is
medical therapy (scrupulous and compliant regulation of lipids, glucose, BP,
and cigarette smoking, as well as
appropriate platelet inhibition).
What might
the primary care clinician advise patients with asymptomatic carotid stenosis?
You have (at
the minimum) one chance in 33 of dying or having a stroke as a result of
surgery.
If you survive the operation and do not have a stroke due to the surgery, your prognosis will be more favorable in the next 5 years if you have successful surgery:
A. Chance of
having a stroke without surgery is 11% over 5 years. (About one in ten)
B. Chance of having a stroke after successful
surgery is 3.8% over 5 years. (About one in 25)
Chances of
harm and benefit are equal for the first 2 years.
If you are elderly (over75), there is a much
greater chance of your dying of a cause other than stroke. RTJ
STRONTIUM (See OSTEOPOROSIS [1-13])
TAMSULOSIN (Flomax)
(See RENAL COLIC)
TESTOSTERONE (See HYPOGONADISM)
THROMBOEMBOLIC DISEASE (See VENOUS THROMBOEMBOLISM)
TOLVAPTAN (See HEART FAILURE [4-11])
TRANSIENT ISCHEMIC ATTACK (TIA) (See STROKE [2-2 AND 2-3]
6-10 FONDAPARINUX OR ENOXAPARIN FOR THE INITIAL
TREATMENT OF SYMPTOMATIC DEEP VENOUS THROMBOSIS
Fondaparinux
is a selective inhibitor of activated factor X (Xa). Once-daily injections produce
a predictable anticoagulant effect.
This randomized, double-blind multicenter
study entered over 2200 patients (mean age 61) with established
acute
symptomatic DVT of the lower extremity. Randomized to fondaparinux once-daily,
or the low-molecular-weight heparin enoxaparin twice-daily. Many received injections at home. All were
started on oral anticoagulant therapy within 72 hours.
Double-blind subcutaneous injections were
continued for at least 5 days, or until the warfarin-induced INR
reached
2.0 or greater. Oral therapy was continued for 3 months
Over 3 months, outcomes were very similar between
groups: recurrent thromboembolic
events, pulmonary embolism, recurrent DVT, major bleeding, and death.
“This study adds to the growing body of
evidence that inhibitors of activated factor X are effective, safe, and
easy-to-use antithrombotics.”
There
are several cautions about at-home treatment with either LMWH or fondaparinux:
1) concern about undertreatment of DVT and resultant pulmonary embolism, and 2)
the need for careful laboratory monitoring of oral anticoagulation status
during the first days of treatment.
Should
fondaparinux be considered a “me too” drug?
For a new drug to be adopted into primary care practice to replace an
old effective drug, important attributes must be considered—must be just as
effective, or more effective; must be
established as just as safe or safer; must be more convenient to administer and
require fewer doses; must be less costly.
Study
sponsored by Sanofi-Synthelabo and MV Organon.
I always look for “spin” in drug-company sponsored studies. This study
looks straight forward. We look for confirmation. RTJ
Multilayered elastic compression bandaging, leg
elevation, and exercise achieve healing in up to 80% at 24 weeks. However,
despite continued use of elastic compression stockings, the 12-month recurrence
rate is high. .
Simple
superficial venous surgery (saphenous vein ablation) theoretically removes the
underlying venous incompetence in legs in patients with isolated superficial
reflux.
This randomized study reported that healing over 24
weeks was similar between groups. Recurrence of the ulcer within 1 year was
much less likely in the surgery group. [NNT = 6]
The
investigators state that about a quarter of patients with venous ulcers will
refuse surgery. Primary care clinicians then deal with these individuals as
best they can. RTJ
VIRTUAL COLONOSCOPY (See COLONOPSCOPY [4-2])
4-5 EFFECT OF VITAMIN D ON FALLS
This meta-analysis of randomized,
controlled trials concludes that vitamin D supplementation reduces risk of
falling in elderly persons. Based on 5 of the trials in over 1200 persons,
vitamin D, was associated with a reduction in rate of falls by 22%.
In two studies, vitamin D plus calcium
(compared with calcium alone) improved body sway by 9% within 2 months, and
increased muscle function up to 11%.
What is a possible mechanism? 1,25-hydroxyvitamin
D, the active metabolite, binds to a highly specific nuclear receptor in muscle
tissue. This may mediate de novo protein synthesis through this specific
nuclear receptor leading to an increase in the number, size and strength of
muscle fibers. This benefit may occur within several months. (Too early to be attributed to increased bone
strength.)
I considered this a weak study, but
interesting. If indeed vitamin D strengthens muscle and thus prevents falls,
its benefit/harm-cost ratio (which is already high.) will be substantially
increased.
Vitamin D
and calcium intake is generally too low in the US population. I believe that
supplementation is warranted in persons of all ages to help maintain bone mass
and strength. If muscles are strengthened, so much the better. RTJ
1-16 POISED TO CHALLENGE NEED FOR SLEEP,
“WAKEFULNESS ENHANCER” ROUSES CONCERN
The
drug maker Cephalon has made an
unusual request. It wants the FDA to approve a drug, not for a condition or a
disease, but for a symptom—sleepiness. Not just routine sleepiness, but
excessive, or “profound sleepiness”—the kind that makes drivers crash.
The drug is modafinil. It is marketed as Provigil. It is already approved for the
treatment of narcolepsy. Modafinil somehow—no one knows how—targets the
hypothalamus and other sleep-regulating areas of the brain. Patients feel more
alert without “hyperarousal”.
According to sales figures, more and more
sleep experts, psychiatrists, and primary care clinicians are prescribing
modafinil for sleepiness for conditions other than narcolepsy. Depression tops
the list.
Cephalon’s trials reported few adverse effects. A handful of
patients discontinued because of headache and nausea. Modafinil induces the P450 system in the liver and may affect
metabolism of many drugs. Caution is advised in patients with left ventricular
hypertrophy, ischemic heart disease and hypertension. There is an abuse
potential. The drug has psychoactive and euphoric effects in some patients.
Modafinil is classified as a schedule IV
drug. Long-term studies are limited. The drug blurs the lines between illness
and enhancement.
Provigil taken regularly costs several hundreds of dollars per
month. The company is ramping up for a marketing blitz which includes
direct-to-consumer advertising.
I do not
believe primary care clinicians should prescribe this drug. Wait for further
experience. RTJ