PRACTICAL POINTERS
FOR
PRIMARY CARE
ABSTRACTED MONTHLY FROM THE JOURNALS
AUGUST 2005
CHRONIC INSOMNIA Pharmacological Treatment
COMBINATION AND SEQUENTIAL THERAPY FOR OSTEOPOROSIS Alendronate and Parathyroid Hormone
ROCKY MOUNTAIN
SPOTTED FEVER A Newly Described Vector
JAMA, NEJM, BMJ, LANCET PUBLISHED BY PRACTICAL
POINTERS, INC.
ARCHIVES
INTERNAL MEDICINE EDITED BY RICHARD T. JAMES JR. MD
ANNALS INTERNAL MEDICINE
[email protected] DAVIDSON
NC 28036
www.practicalpointers.org
This document is divided into two parts:
1) The Highlights
section contains brief comments patterned after the “abstract” placed on
the first page of many studies reported in journals. Highlights condenses the content of studies, and allows a
quick review of pertinent points of each article.
The Editorial Comments are the editor’s assessments of the clinical practicality
of articles based on his long-term review of the current literature and his
20-year publication of Practical Pointers.
2) The main Abstracts
section is designed as a reference. It presents structured summaries of the
content of articles in much more detail.
An Index containing all the Highlights is published twice a year. In
an evening or two, the reader can refresh memory of the entire content of
practical points abstracted from 6 major journals over the 6-month period.
I hope you will find Practical Pointers interesting and
helpful. The complete content of all issues for the past 5 years can be
accessed at www.practicalpointers.org
Richard T. James Jr, M.D.
Editor/Publisher.
HIGHLIGHTS AND EDITORIAL COMMENTS AUGUST
2005
CPGs Give Little Guidance For Care Of
Older Patients.
As the population
ages, the prevalence of patients with multiple chronic medical conditions
increases.
Previous studies reported that up to half of Medicare patients aged 65 and
older have at least 3 chronic medical conditions. One fifth has 5 or more.
Difficulties rise as the number of diseases increases.
Physicians who care for older adults
with multiple diseases must strike a balance between following CPGs and
adjusting recommendations for individual patients’ circumstances.
This study evaluated the
applicability of 9 CPGs to the care of older individuals. Only 4 of The 9 CPGs included
in the study addressed older individuals with comorbidities. Many did not
discuss the quality of evidence underlying the recommendations for older
patients.
None of the CPGs discussed the burden
of comprehensive treatments on patients and caregivers. None discussed
balancing short- and long-term goals such as when short-term quality of life is
better without a treatment even if that treatment might lengthen life.
The authors generated a possible
treatment schedule that would result if all the recommendations of the CPGs
were followed in patients with 5 or more comorbid conditions. Developing a
treatment plan for a hypothetical patient in accordance with CPGs would result
in treatment with multiple drugs with a high complexity of administration. This could increase risks of medication
errors, adverse drug events, drug interactions, and hospitalizations.
Independent self-management and adherence would be difficult. The treatment burden might be unsustainable.
“CPGs do not provide an appropriate,
evidence-based foundation for assessing quality of care
in older adults with several chronic
diseases.” Although they provide detailed guidance for managing a single
disease, they fail to address the needs of older patients with complex comorbid
illnesses. CPGs rarely address treatment of patients with 3 or more chronic
diseases—a group that includes half of the population over the age of 65.
This is not to say that CPGs are not valuable—only that their value is
restricted.
I believe that elderly patients take too many drugs. Many continue to
take drugs which have outlived their benefit. As we get old and older, the
benefit/harm-cost ratio of drugs and interventions changes. The probability of
benefits falls; the probability of adverse effects increases; and costs may
become more burdensome.
I believe that some elderly persons, especially the very elderly, who
feel reasonably well and cherish each day of the “precious few” that remain,
would opt to be left in peace, and not risk being subjected to tests,
examinations, surgical interventions, and drugs and treatments with adverse
effects that might undermine their present quality of life. There is a
trade-off between maintaining the present quality-of-life by comfort care only
versus interventions which may lengthen life at the risk of decreasing present
quality of life. This is a personal decision.
Realizing that the remaining days of my life are limited, I would not
trade one day of quality-life at age 85 for 50 days of poor health at age
95 likely to be associated with
increasing dependency, dementia, and loss of dignity.
At present, much of daily medical practice addresses the indications for
treatment of a single disease or symptom. Many older patients expect and
request a “pill for every ill”. They should understand that this may lessen
their present quality of life. It may be preferable to bear some of the symptoms
and go on with daily living.
Healthy life-styles should continue.
Primary care clinicians must understand the choices and goals of each
individual patient. The goal is to extend days-of-quality-life, not days-of-life.
The “art” of medicine must continue unabated.
A Review of Newer Pharmacological Agents
Duration of action Half-life (hr) Dose (mg) Indications
1) Restoril (tamezepam) Intermediate 8-15 7.5-30 Sleep maintenance
May be tried for
insomnia associated with difficulty in maintaining sleep. The greatest effect is on total
sleep time. May soon be supplanted by Lunesta. Short-term
tolerance, measured by deterioration in sleep measures over time, has not been
noted after use for 8 weeks. Daytime
sleepiness, dizziness, and incoordination may occur
with the intermediate-acting agents, but are not common.
The FDA has approved use for up to 10 days
2) Lunesta (eszopiclone)
Intermediate 5-7 1-3 Sleep
maintenance
A 6-month study of Lunesta showed a
50% reduction in sleep-latency (onset of sleep) and a 65% reduction in wake
time after onset of sleep. The greatest effect was on total sleep time. After 6 months, a sustained beneficial effect
without development of tolerance was reported.
Daytime sleepiness, dizziness, and incoordination
may occur with the intermediate-acting agents, but are not common.
(I was unable to find any limitations
by the FDA for duration of use. RTJ)
3) Ambien (zolpidem) Short 3 5-10 Sleep
onset
Studies of Ambien used
intermittently (3 to 5 times a week) report effectiveness in chronic insomnia,
with sustained benefits on nights the drug is taken, and sleep that is no worse
than baseline on nights without medication No rebound insomnia was reported
after discontinuation. The greatest effect is on sleep latency. (Difficulty in going to sleep.) Amnesia, including that associated with
sleep-related eating, has been described rarely. Adverse effects (drowsiness, dizziness, and incoordination) are less frequent with use of short acting
drugs and generally occur after high dose.
Short-term tolerance, measured by deterioration in sleep measures over
time, has not been noted after continuous use for 4 weeks,
and intermittent use for 12 weeks.
The FDA has approved use for up to 10
days
4) Sonata (zaleplon) Ultra short 1 5-20 Sleep
onset and maintenance
Sonata may have effects in reducing the time to go to sleep, but may have no
significant effect on total sleep time.
Because of its very short half-life, it may be given on awakening during
the night, and may not result in any daytime drowsiness or cognitive impairment, Studies report a 50% reduction in sleep
latency. Administered 3.5 hours after
lights out, with 4 hours more sleep permitted, it did not result in any daytime
drowsiness or cognitive impairment. No
rebound insomnia reported.
Use for 6 months showed a
sustained benefit without development of tolerance. Adverse effects (drowsiness,
dizziness, and incoordination) are less frequent with
use of short acting drugs and generally occur after high dose.
The FDA has approved use for up to 10
days
I believe these newer sleep medications will be increasingly prescribed
by primary care clinicians.
To fit the drug to the sleep difficulty, we should ask the patient
whether they have difficulty in sleep onset, or difficulty in sleep
maintenance. Sonata may be a useful first choice for the former, and Lunesta of
the latter.
Several of the author’s comments interested me: 1) Use for secondary insomnia when
elimination of the cause is not achievable. 2) “Off label” use (over ten days) for
Ambien and Sonata. 3) Many sleep
specialists recommend long-term use of pharmacological therapy in a subgroup of
patients who do not respond to cognitive behavioral therapy This would also include patients for whom
cognitive behavioral therapy is simply not an available means of therapy—ie,
most patients consulting primary care clinicians.
I believe many primary care clinicians prescribe “sleeping pills” freely
and for periods longer than approved. Clinical judgment is required. Several
different drugs may be prescribed on a trial-and-error basis. We can now fit
the pill to the patient. Intermittent therapy is preferable. I wonder…Would
switching periodically from one to another be advantageous?
Bone Turnover Increases with
Teriparatide; Decreases
with Alendronate. Both Lead to Increased BMD.
8-3 OPPOSITE
BONE REMODELING EFFECTS OF TERIPARATIDE AND ALENDRONATE IN INCREASING BONE MASS
Imbalances in the bone remodeling
process affect mechanical properties related to bone strength, including bone
geometry and microarchitecture. When bone resorption exceeds bone formation, osteoporosis
results, and the risk of fracture increases.
Therapies can preferentially modulate
1) bone resorption (eg, alendronate) or 2) bone formation (eg, teriparatide; human recombinant parathyroid hormone). Both
correct the imbalances in the bone remodeling process.
This study compared the biochemical
effects of both drugs and their effects on bone mineral density (BMD).
Alendronate suppressed
bone turnover. It inhibited bone resorption after one month and inhibited
formation at 3 months. A new steady state was achieved and persisted through 12
months. The effect on inhibition of resorption continued and more than
compensated for the reduction in formation. As a result, BMD increased modestly
in the spine and proximal femur.
Teriparatide increased
bone turnover. It increased the formation of bone which persisted for at least
12 months. Bone resorption also increased modestly for up to 12 months. The
increase in bone formation more than overcame the rate of resorption. As a
result, BMD increased.
Why should we be concerned about the detailed metabolic effects of these
drugs? Because, since
they act differently, their beneficial effect in increasing BMD and bone
strength may be additive. Would use of both drugs, concomitantly or in
sequence, increase BMD and bone strength compared with use of either alone? See the following abstract.
One Year Of
Parathyroid Hormone Followed By One Year Of Alendronate An Effective Means Of
Increasing BMD
8-4 COMBINATION AND SEQUENTIAL THERAPY FOR
OSTEOPOROSIS
Bisphosphonates produce a steady increase in bone
mineral mass averaging about 1% a year for up to 8 to 10 years. And once-daily parathyroid hormone given subcutaneously increases
central bone mass by 8% to 10% per year for up to 2 years.
Combinations of PTH + bisphosphonates
appear to increase central bone mass, but to a lesser extent than with PTH
alone.
When PTH is used alone, in the months
after PTH is discontinued, some or all of the bone gained appears to be lost.
Administering bisphosphonates
after a course of PTH appears to
conserve the bone gained, and adds a further increase in its own right, roughly
similar in magnitude to the short-term effect of bisphosphonates given to
previously untreated patients.
The term “osteoporosis” denotes not
only defects in bone mass, but also defects in “bone quality”. The latter may
be as important as the former in promoting weakness of bone. Both drugs improve
“bone quality”.
An accompanying
article “One Year of Alendronate after One Year of Parathyroid Hormone (1-84)
for Osteoporosis.” NEJM August 1, 2005; 353: 555-65 reports:
1) One year of PTH followed by one
year of placebo:
Patients receiving PTH for one year
gained BMD. During the 2nd
year, when receiving placebo, much of the gain was lost. (Ie,
apparently PTH must be continued to maintain the gain in BMD.)
2) One year of PTH followed by one
year of alendronate:
Patients receiving PTH for one year
gained BMD. During the 2nd year of alendronate-alone
therapy, BMD continued to increase.
3) One year of alendronate
+ PTH followed by one year of alendronate alone:
During the first year of combined
therapy, there was no advantage over PTH alone. Over 2 years, BMD increased,
but at somewhat lower rate than those receiving PTH for one year followed by alendronate.
4) One year of alendronate
followed by a second year of alendronate:
BMD increased over 2 years, but not
as much as in the group receiving 1-year of PTH followed by 1-year of alendronate.
“Thus, from a clinical perspective, one year
of parathyroid hormone followed by one year of alendronate would seem to be an
effective means of increasing bone mineral density while minimizing the use
of parathyroid hormone.”
Note that 2-years of PTH was not used as a
comparator.
More observation is required to determine the most favorable use of
combinations. There seems to be some advantage.
Most of the studies of osteoporosis I have abstracted thus far concern
treatment of the established disease. Prevention is much more important. Making
sure that calcium and vitamin D intakes are adequate during all periods of life
is a start. Would very low-dose bisphosphonate, given perhaps once monthly,
starting at the time of menopause, and continued for years, prevent the disease.?
Should Primary Care Clinicians
Prescribe This Therapy?
After acute coronary events, a marked
thrombin generation state persists for months. This suggests a role for
anticoagulation beyond the initial use of low-molecular-weight heparin.
This study quantified the risks and
benefits of warfarin + aspirin vs aspirin alone after acute coronary syndromes (ACS). Patients considered at high risk
of major bleeding from warfarin therapy were excluded.
Outcomes per 1000 patients per year:
Warfarin + aspirin Aspirin alone Absolute
difference NNT (2 y)
MI 22 41 19 53
Ischemic stroke 4 8 4 250
Major bleeding 1.5 0.6 0.9 1100
Death No difference
I included this abstract mainly to point out why many primary care
clinicians will, with good reason, resist prescribing warfarin in addition to
aspirin for patients with ACS . I believe primary care
clinicians should rarely, if ever, prescribe warfarin for this indication..
1. The NNT to benefit one patient is high. No benefit for mortality.
The cited risk of major bleeding (~ 1 in 1000 per year) is unrealistically low
when applied to primary care. Non-major bleeding will commonly occur and create
anxiety, inconvenience
and additional costs.
2. Patients in primary care differ substantially from those
in trials: They will be at higher risk for bleeding. Exclusion criteria may not be strictly
applied. Patients will be less adherent to laboratory
control; they will be less carefully followed; they may use OTC drugs that are
contraindicated when warfarin is used; they may be more likely to eat foods
which can increase risk of bleeding. Costs and inconvenience may be too high.
3. Many patients in primary care are
elderly, medically indigent, and medically illiterate. Warfarin therapy is not
suitable for these groups.
Primary care clinicians will still apply the many other drug and
lifestyle measures which reduce risk of recurrence of ACS
This is a good example of the “Catch 22” of interventions in primary
care—benefits are often hidden, harms are evident. Physicians and patients would
have no way of knowing which 19 patients of the 1000 treated are the ones that
avoided an MI. On the other hand, patient
and physician alike would be painfully and dramatically aware of bleeding.
Describing a New Dog Vector for One of the Most Virulent Human Infections
Ever Identified.
8-6 ROCKY
MOUNTAIN SPOTTED FEVER – Changing Ecology And
Persisting Virulence
Rocky mountain
spotted fever (RMSF) is one of the
most virulent human infections ever identified. Up to 10% of persons infected
will die. Many more will require intensive care, and have sequelae such as
amputation and permanent learning impairment. This is despite the availability
of a simple and highly effective treatment (doxycycline).
Diagnosis is difficult because of the
non-specific presentation of the disease. Symptoms include fever, headache,
myalgia, and (usually after 3 to 5 days) rash.
The rash evolves from macular to macro-papular, to petechial.
Organ-specific symptoms (nausea, vomiting, abdominal pain, and cough) confound
diagnosis by distracting attention from systemic manifestations. Serologic
analysis is not useful during an active infection.
Early clinical suspicion and
empirical therapy are essential. Severe illness and death are associated with a
delayed diagnosis, which may occur because of absence of a rash or presentation
during a season with a low level of tick activity.
An accompanying study describes a new
vector for RMSF—the brown dog tick which differs from the American dog tick.
The brown dog tick is intimately related to households.
“No longer can we consider RMSF a
disease of only rural and southern venues; it has emerged and re-emerged
again.”
This is a caution aimed mainly at primary care clinicians. They should
maintain a high degree of suspicion about the possibility of RMSF. On
consultation by an acutely and seriously ill, previously well patient
(especially a young patient with a rash), asking about ticks in the environment
and tick bites should be routine.
As a public health measure, if ticks are prevalent, measures to eliminate
them should be taken.
Since there is no confirmatory test immediately available, empiric
treatment with antibiotic (doxycycline) is justifiable because the stakes are
high. The outcome of unrecognized RMSF may be disastrous.
RMSF is defined as an infection caused by R rickettsii. But R rickettsii
is not the only rickettsia carried by arthropods which can cause disease.
Correspondence in this issue (NEJM August 1, 2005 pp 626-27) lists 6 different
species. More unnamed species may exist.
ABSTRACTS AUGUST 2005
CPGs Give Little Guidance For Care Of Older Patients.
8-1 CLINICAL PRACTICE GUIDELINES AND QUALITY OF
CARE FOR OLDER PATIENTS WITH MULTIPLE COMORBID DISEASES
As the population
ages, the prevalence of patients with multiple chronic medical conditions
increases. Previous
studies reported that up to half of Medicare patients aged 65 and older have at
least 3 chronic medical conditions. One fifth has 5 or more. Difficulties rise
as the number of disease increases.
Clinical practice guidelines (CPGs) are based on clinical evidence
and expert consensus to help decision making about treating specific
diseases. Most CPGs address single
disease in accordance with modern medicine’s focus on evidence, based on
randomized controlled trials. However, physicians who care for older adults
with multiple diseases must strike a balance between following CPGs and
adjusting recommendations to individual patient’s circumstances.
This study evaluated the
applicability of CPGs to the care of older individuals with several comorbid
diseases. Data sources included a national survey which identified the most
prevalent chronic diseases and a National Guideline Clearinghouse to locate
evidence-based CPGs for each chronic disease.
The authors analyzed 7 of the most
common chronic conditions: heart failure, stable angina, atrial fibrillation,
diabetes, osteoarthritis, chronic obstructive pulmonary disease, and
osteoporosis. These are usually managed in primary care. They chose CPGs
promulgated by national medical organizations for each condition.
They abstracted data about
applicability of the CPGs to individuals aged 65 and older with multiple
comorbid diseases. This included indications for treatment, feasibility of
treatment, and duration of therapy necessary to achieve benefit in the context
of life expectancy. They considered the patient-centered aspects of decision
making including effects of quality of life, physical functioning, pain,
differentiation between short- and long-term effects, and goals of treatment
(cure, arresting progression, preventing complications, managing symptoms).
They considered patient preferences, shared decision making, and the burden of
following recommendations (both by the patient and by care givers).
A hypothetical patient was
considered—a 79-year old female with osteoporosis, osteoarthritis, diabetes,
hypertension, and chronic obstructive pulmonary disease. They abstracted
recommendations for each condition from 9 CPGs, and assembled a comprehensive
treatment plan using explicit instructions from relevant CPGs. They tried to
reduce complexity of the program and chose the least expensive medications with
the fewest adverse effects.
RESULTS
Applicability of CPGs:
Only 4 of 9 CPGs addressed older
individuals with comorbidities. Many did not discuss the quality of evidence
underlying the recommendations for older
patients. Only the diabetes CPGs discussed the relationship between life
expectancy and the time needed to treat to achieve benefit.
Inclusion of patient-centered domains in CPGs:
None of the CPGs discussed the burden
of comprehensive treatment on patients and caregivers. None discussed balancing
short- and long-term goals such as when short-term quality of life is better
without a treatment even if that treatment provides long-term benefits.
Applying CPGs to the hypothetical patient:
The authors generated a possible
treatment schedule that would result if all the recommendations of the CPGs
were followed. The patient would take 12 separate medications. This would
require 19 doses per day, taken at 5 different times. In addition, the program
would include 14 different non-pharmacological activities (educational,
nutritional, rehabilitative,
monitoring, and visiting specialists). Concurrent adherence to
all CPGs would result in potential interactions between drugs, and between food
and medications. Some recommendations contradicted each other. The cost of
drugs would exceed $400 a month (almost $5000 a year).
DISCUSSION
“CPGs do not provide an appropriate,
evidence-based foundation for assessing quality of care in older adults with
several chronic diseases.” Although they provide detailed guidance for managing
single diseases, they fail to address the needs of older patients with complex
comorbid illnesses. CPGs rarely address treatment of patients with 3 or more
chronic diseases—a group that includes half of the population over the age of
65.
Developing a treatment plan for a
hypothetical patient in accordance with CPGs may result in treatment with
multiple drugs with a high complexity of administration. This could increase risks of medication
errors, adverse drug events, drug interactions, and hospitalizations.
Independent self-management and adherence would be difficult. The treatment burden might be unsustainable.
CPGs are designed largely by specialty-dominated
committees for managing single diseases.
The use of CPGs to evaluate the
quality of care given by individual clinicians, and to
determine physician reimbursement through pay-for-performance measures could
create inappropriate incentives for care.1 CPGs are not
designed for use in quality assessment. Transforming CPGs into performance
standards and applying these standards to care of older patients with chronic
conditions is problematic. CPGs are based on varying levels of evidence and assume
application of clinical judgment and patient preference—both of which would be
difficult to measure.
Quality indicators must balance
scientific evidence against what is practical and feasible.
Measurement of quality of care should
place emphasis on weighing burden, risks, and benefits of complex therapies—and
on sharing decision making with patient and family.
Standards for developing CPGs note
the importance of improving adherence by both physicians and patients, identifying
the target population, and incorporating quality of life and patient
preferences. The CPGs examined in this study did not give explicit guidance on
how to do this.
JAMA August 10, 2005; 294:
716-24 “Special Communication”
original investigation, first author Cynthia M Boyd, Center on Aging and
Health,
1 The Medicare Payment Advisory
Commission has recommended that Medicare adopt a pay-for-performance
for physician reimbursement. The authors consider this ill-advised.
An editorial in this issue of JAMA by
Patrick J O’Connor, Healthpartners Research Foundation,
The National Guideline Clearinghouse
(sponsored by the Agency for Healthcare Research and Quality) now lists over
1650 active CPGs—386 for diabetes alone. Most are based on studies limited to a
single clinical intervention.
For the many individuals who have
multiple medical problems, following the guidelines proposed for each problem
leads to complex drug treatment schedules, multiple physician visits, high
costs, and disruption of daily routines—all of which invite non-adherence.
There is much redundancy and
significant variation in recommendations across multiple
CPGs. CPGs are often embedded in lengthy documents that are not easily
accessible at the point of care. “The most onerous problems that physicians who
use CPGs now face include: too many evidence-based recommendations,
recommendations that are sometimes inappropriate in particular clinical situations, and recommendations that often are not ranked in
terms of their clinical value.”
Benefits documented in clinical
trials are “average” benefits. Even within the trials, the degree of benefit
received from an intervention depends on many patient-specific factors.
Practicing physicians care for patients with greater patient-specific variation
than the subjects in clinical trials on which CPGs are based. The trials require restrictive eligibility
criteria.
All recommendations are not of equal
clinical value to all individual patients. Benefit estimates should take into
account patient-specific factors such as age, estimated life expectancy,
baseline risk of complications, and the complexity of a therapeutic regimen.
“This is especially important for frail elderly patients with multiple chronic
conditions, who may be unable or unwilling to tolerate, afford, or adhere to a
large number of pharmacological and lifestyle interventions over long periods.”
“Holding physicians accountable for
hundreds of process and outcome measures could divert clinical attention from
the few key interventions that are of most potential benefit to a patient, and
might multiply costs of care with minimal positive effect on health.”
Despite their limitations,
evidence-based CPGs remain an important and necessary tool in the effort to
improve health care quality. Customization of care in complex clinical
scenarios respects the individuality of patients and the professional judgment
of highly skilled physicians and minimizes the problem of overtreating patients
most susceptible to drug interactions, drug adverse effects, and medical error.
==============================================================================
A Review of Newer Pharmacological Agents
8-2 CHRONIC INSOMNIA
Clinical studies adopt arbitrary
definitions of insomnia. In practice, the patient’s subjective judgment of
sleep quality and quantity is a more important factor.
Chronic insomnia (lasting over one
month) has a prevalence of 10% to 15%. It is more common in women and the
elderly. It may have adverse consequences—fatigue, mood disturbances, problems
with interpersonal relationships, occupational difficulties, and reduced
quality of life.
Studies suggest that patients with primary insomnia differ from
controls—increased global cerebral glucose metabolism on PET scan, differences
in electroencephalographic patterns, increased 24-hour metabolic rate, and
higher levels of secretion of adrenocorticotropic hormone and cortisol.
Insomnia secondary to other causes is more common than primary insomnia. (Eg,
psychosocial stress, poor sleep hygiene, psychiatric disorders, medical
conditions, and insomnia related to use of other drugs.) However…“If insomnia persists despite
treatment of secondary causes, then therapy for primary insomnia should be
instituted.”
Pharmacological therapy:
The article presents a useful list of select
FDA-approved medications for insomnia in table 3, page 806. Restoril is a
benzodiazepine. The others, while technically not benzodiazepines (their
chemical structures differ) are termed benzodiazepine-receptor agonists. All
act by binding to the gamma aminobutyric-acid receptor. Some are relatively
new.
Duration of action Half-life (hr) Dose (mg) Indications
1) Restoril
(tamezepam) Intermediate 8-15 7.5-30 Sleep
maintenance
May be tried for
insomnia associated with difficulty in maintaining sleep. The greatest effect is on total
sleep time. May soon be supplanted by Lunesta. Short-term tolerance, measured by deterioration in
sleep measures over time, has not been noted after use for 8 weeks. Daytime sleepiness, dizziness, and incoordination may occur with the intermediate-acting
agents, but are not common.
The FDA has approved use for up to 10 days
2) Lunesta (eszopiclone)
Intermediate 5-7 1-3 Sleep
maintenance
A 6-month study of Lunesta showed a 50% reduction in
sleep-latency (onset of sleep) and a 65% reduction in wake time after onset of
sleep. The greatest effect was on total sleep time. After 6 months, a sustained beneficial effect
without development of tolerance was reported.
Daytime sleepiness, dizziness, and incoordination
may occur with the intermediate-acting agents, but are not common.
(I was unable to find any limitations
by the FDA for duration of use. RTJ)
3) Ambien (zolpidem) Short 3 5-10 Sleep onset
Studies of Ambien used
intermittently (3 to 5 times a week) report effectiveness in chronic insomnia, with
sustained benefits on nights the drug is taken, and sleep that is no worse than
baseline on nights without medication No rebound insomnia was reported after
discontinuation. The greatest effect is on sleep latency. (Difficulty
in going to sleep.) Amnesia,
including that associated with sleep-related eating, has been described
rarely. Adverse effects (drowsiness,
dizziness, and incoordination) are less frequent with
use of short acting drugs and generally occur after high dose. Short-term tolerance, measured by
deterioration in sleep measures over time, has not been noted after continuous
use for 4 weeks, and intermittent use for 12 weeks.
The FDA has approved use for up to 10
days
4) Sonata (zaleplon) Ultra short 1 5-20 Sleep onset and maintenance
Sonata may have effects in reducing the time to go to sleep, but may have no
significant effect on total sleep time.
Because of its very short half-life, it may be given on awakening during
the night, and may not result in any daytime drowsiness or cognitive impairment, Studies report a 50% reduction in sleep
latency. Administered 3.5 hours after
lights out, with 4 hours more sleep permitted, it did not result in any daytime
drowsiness or cognitive impairment. No
rebound insomnia reported.
Use for 6 months showed a
sustained benefit without development of tolerance. Adverse effects (drowsiness,
dizziness, and incoordination) are less frequent with
use of short acting drugs and generally occur after high dose.
The FDA has approved use for up to 10
days
Many trials have shown the efficacy
of these drugs in relieving short-term insomnia. A meta-analysis demonstrated
significant improvements in sleep latency, total sleep time, number of
awakenings, and sleep quality, compared with controls, A
high percentage of patients fell asleep faster, slept longer, woke less often,
and reported better sleep quality.
The relatively short duration of
studies has been problematic. None have extended beyond 6 months. The short-acting agents have the greatest
effect on sleep latency; intermediate- and long-acting have the greatest effect
on total sleep time.
All are contradicted in pregnancy. They
should not be combined with alcohol. Use lower doses in the elderly and in
debilitated patients.
All may have adverse effects—drowsiness,
dizziness, incoordination—less commonly associated with short acting drugs.
Withdrawal effects, especially rebound insomnia, tend to be mild after the
discontinuation of the intermediate-acting drugs. Marked rebound insomnia has
been reported after discontinuation of triazolam (Halcion), a short acting benzodiazepine. Anterograde amnesia the
day after has also been reported.
Non-prescription products marketed
for treatment of insomnia include melatonin and the sedating histamine
antagonists [eg, diphenhydramine (Benadryl),
doxylamine (Unisom)]. Use of these drugs is not supported by
rigorous data. The histamine-receptor antagonists may improve sleep
subjectively, but conclusions are limited by a small number of subjects, a
short duration of administration, and lack of objective measurements. Morning
sedation is a side effect. Studies of melatonin have reported conflicting
results.
The benzodiazepines, flurazepam (Dalmane; generic) and quazepam ( Serax) are also
approved by the FDA for treatment of insomnia, but because of their long
half-life, they are generally not recommended.
Sedating tricyclic
antidepressants [trazodone (Desyrel)
and doxepin (Sinequan
)] have been increasingly used for chronic insomnia for treatment of
insomnia in depressed patients. There is a paucity of studies to support their
use. Adverse effects are common.
A new melatonin-receptor agonist has
been approved— Rozerem
(ramelteon). More time will be needed to
determine its place in management.
The author spends considerable time
discussing cognitive behavioral therapy for treatment of insomnia. Primary care
clinicians will find application of cognitive behavior therapy difficult to
apply in the busy flow of practice. Referral to specialists (if available) may
be considered. “Although long-term data are lacking, most sleep specialists
recommend long-term use of pharmacologic therapy in a subgroup of patients with
chronic primary insomnia who do not respond to cognitive behavioral therapy.”
“For insomnia that is predominantly
associated with onset of sleep, off-label use of Ambien and Sonata (ie,
longer than 10 days) should be considered.” For insomnia that is predominantly
associated with maintenance of sleep, intermediate-acting drugs (eg, Restoril) can be tried. But these drugs
may soon be supplanted by Lunesta.
There is little role for use of
long-acting benzodiazepines in management of insomnia unless a coexisting
anxiety disorder is present.
NEJM August 25, 2005; 353:
803-10 “Clinical Practice” review
article by Michael H Silber, Mayo Clinic College of Medicine,
============================================================================
Bone Turnover Increases with Teriparatide; Decreases with Alendronate. Both Lead to Increased BMD.
8-3 OPPOSITE BONE REMODELING EFFECTS OF
TERIPARATIDE AND ALENDRONATE IN INCREASING BONE MASS
Imbalances in the bone remodeling
process affect mechanical properties related to bone strength, including bone
geometry and microarchitecture. When bone resorption exceeds bone formation,
the risk of fracture increases.
Therapies can preferentially modulate
1) bone resorption (eg, alendronate) or 2) bone formation (eg, teriparatide). Both correct the imbalances
of the bone remodeling process which occur in osteoporosis.
This study compared the biochemical
effects of both drugs and their effects on bone mineral density (BMD).
Conclusion: Two distinct options for the management of
osteoporosis lead to increases in BMD by opposite mechanisms of action.
STUDY
1. Randomized, parallel,
double-blind study followed over 200 postmenopausal women with osteoporosis for
18 months. (Mean age = 66; T score -2.5 to -4.0 at the lumbar spine and femoral
neck.) All received supplementary calcium and vitamin D.
2. Randomized to: 1) teriparatide (Forteo, recombinant human parathyroid hormone 1-34; 20 mg daily subcutaneously),
or 2) alendronate (Fosamax, a bisphosphonate; 10
mg daily by mouth).
3. Compared effects on bone turnover of alendronate vs
teriparatide by measuring:
A. Two biochemical
markers of bone turnover: 1) a marker of bone formation, and 2) a marker of
bone resorption.
(See text)
B. Bone mineral density (BMD) by both:
1. Area (grams per square centimeter)
by dual-energy X-ray absorptiometry, and
2. Volume (per cubic centimeter) by
quantitative computed tomography—a measure of trabecular BMD).
RESULTS
1. Biochemical markers of bone turnover (at 12 months):
Alendronate decreased bone turnover. It decreased both markers.—formation as
well as resorption. The effect on impeding resorption overbalanced the effect on
inhibiting formation. BMD increased modestly.
Teriparatide increased
bone turnover. It increased both markers—formation and resorption. The rate of
formation overbalanced the effect on resorption. BMD increased.
2. Bone mineral density (means at 18 months): Alendronate Teriparatide
Lumbar spine
Area BMD + 5% +10%
Trabecular BMD +
4% + 19%
Femoral neck
Area BMD + 3.9% + 3.5%
Trabecular volumetric BMD +
2.2% + 5%
Cortical volumetric BMD + 8% - 1%
3. Adverse effects: Both were safe and well tolerated. Withdrawals
were about equal. One interesting difference—more patients in the alendronate
group reported new or worsening back pain during treatment (39% vs 26%). [The
authors offer no explanation.]
DISCUSSION
1. The improvement in BMD from the two drugs is mediated by
distinct and opposite effects on
bone cell activity. Biochemical markers
of bone turnover reflect the different mechanisms of action:
Alendronate was associated with a reduction in biochemical markers of both
bone resorption and formation. The effect on reducing resorption outweighed
the effect on reducing formation. BMD increased.
Teriparatide was associated with an increase in biochemical markers of both
bone formation and bone resorption. The effect on increasing
bone formation outweighed the effect on increasing bone resorption.
BMD increased.
2. A greater increase in
trabecular BMD was observed with teriparatide. Cortical BMD in the femoral neck
increased more with alendronate.
3. These results do not
provide evidence about the comparative fracture-protection effectiveness of the
two drugs. Previous studies reported a benefit in reducing risk of fracture.
CONCLUSION
The two drugs accomplish their
benefits by different and opposite effects on bone metabolism. Bone turnover increases with teriparatide, and decreases with
alendronate. Both lead to increased BMD.
Archives Int Med August 8-22 2005; 165: 1762-68 Original investigation, first author Michael
R McClung,
============================================================================
One Year Of Parathyroid Hormone
Followed By One Year Of Alendronate An Effective Means Of Increasing BMD
8-4 COMBINATION AND SEQUENTIAL THERAPY FOR
OSTEOPOROSIS
Over the past 10 years, five agents
have been approved for the treatment or prevention of osteoporosis. As a group,
these drugs have revolutionized the management of osteoporosis.
They fall into 2 broad categories:
1) Agents that reduce exaggerated
bone remodeling by impeding bone resorption.
Eg, bisphosphonates
2) Agents that stimulate bone
formation.
Eg, parathyroid hormone (PTH 1-34—the
FDA approved drug— limited by the FDA to two years of use.)
Bisphosphonates produce a steady increase in bone
mineral mass averaging about 1% a year for up to 8 to 10 years. And once-daily parathyroid hormone given subcutaneously increases
central bone mass by 8% to 10% per year for up to 2 years. (The duration of time for which data are available.)
As monotherapy, both classes of
agents are effective in reducing risk of fracture.
It has not been established whether these
drugs enhance each other’s effects if given together or in certain sequences.
Two articles in this issue of NEJM1,2
provide important, but incomplete and preliminary information about the effects
of combinations and sequences of drugs:
1) Combinations of PTH +
bisphosphonates appear to increase central bone mass, but to a lesser extent than
PTH alone.
2) When PTH is used alone,
in the months after PTH is discontinued, some or all of the bone gained appears
to be lost.
3) Administering bisphosphonates after
a course of PTH appears to conserve the bone gained, and adds a further
increase in its own right, roughly similar in magnitude to the short-term
effect of bisphosphonates given to previously
untreated patients.
4) PTH appears to
maintain its anabolic effect in patients previously treated with a
bisphosphonate.
The authors note that these
conclusions reflect the effects of the drugs on bone mass alone. There are
strong reasons to conclude that the antifracture efficacy of both classes of
agents derives, in part, from effects distinct from mass changes. In addition
to producing a small increase in bone mass, bisphosphonates reduce the number
of active remodeling loci on bone surfaces. A reduction in the number of these
loci produces a prompt decrease in bone fragility, independent of their effect
on bone mass. In addition to increasing trabecular bone volume, PTH also increases
the periosteal diameter at critical bone sites.
Defects in “bone quality” probably
equal or even outweigh the mass defect in bone implied in the term
“osteoporosis”.
Osteoporosis is a multifactorial
disorder, unlikely to be controlled by any single class of medication.
NEJM August 11, 2005; 353:
624-25 Editorial, first author
Robert P Heaney,
1 “One Year of Alendronate after One Year of Parathyroid Hormone
(1-84) for Osteoporosis.” NEJM
The FDA limits use of PTH for
treatment of osteoporosis to two years. Should antiresorptive therapy follow
PTH therapy?
The trial considered 4 groups of
women:
1) One year of PTH followed by one
year of placebo:
Patients receiving PTH for one year
gained BMD. During the 2nd
year, when receiving placebo, much of the gain was lost. (Ie, apparently PTH
must be continued to maintain the gain in BMD.)
2) One year of PTH followed by one
year of alendronate:
Patients receiving PTH for one year
gained BMD. During the 2nd year of alendronate-alone therapy, BMD
continued to increase.
3) One year of alendronate + PTH
followed by one year of alendronate alone:
During the first year of combined
therapy, there was no advantage over PTH alone. Over 2 years, BMD increased,
but at somewhat lower rate than those receiving PTH for one year followed by alendronate.
4) One year of alendronate followed
by a second year of alendronate:
BMD increased over 2 years, but not
as much as in the group receiving 1-year of PTH followed by 1-year of
alendronate.
“Thus, from a clinical perspective, one year
of parathyroid hormone followed by one year of alendronate would seem to be an
effective means of increasing bone mineral density while minimizing the use
of parathyroid hormone.”
BMD is a secondary endpoint. The important primary endpoint is the effect
on fracture—not reported in this study.
A previous trial by the same investigators reported that the combination
of alendronate + PTH during one year did not provide a clear advantage over
either one given alone.
2 “Daily and Cyclic Parathyroid Hormone in Women
Receiving Alendronate” NEJM August 11,
2005; 353: 566-75 Original
investigation, first author Felicia Cosman, Helen Hayes Hospital, West
Haverstraw, NY.
This study concerned women who had
taken alendronate for one year.
Randomized for an additional 15 months
to 1) continued alendronate; 2)
continued alendronate + PTH (1-34) given daily;
or 3) continued alendronate + PTH given cyclically three months on,
three months off.
In both PTH groups, BMD in the lumbar
spine rose more than in the alendronate-alone group. BMD rose comparably in
both PTH groups. Many women with osteoporosis
previously treated with alendronate, who are at continued risk of fracture, may
benefit from PTH.
The authors concluded that both
continuous and cyclic PTH combined with alendronate increase BMD. Cyclic
administration may be less costly.
====================================================================================
Should Primary Care Clinicians Prescribe This Therapy?
8-5 WARFARIN PLUS ASPIRIN AFTER MYOCARDIAL INFARCTION
OR ACUTE CORONARY SYNDROME: Meta-analysis with Estimates of Risk and Benefit.
Several interventions are beneficial
in the secondary prevention of myocardial infarction (MI): beta-blockers, ACE inhibitors, statin drugs, and aspirin.
After acute coronary events, a marked
thrombin generation state persists for months. This suggests a role for
anticoagulation beyond the initial use of low-molecular-weight heparin.
Evidence for use of warfarin in this
context has been conflicting. Warfarin use has not been widely adopted, perhaps
because of fear of increased risk of bleeding, or belief that benefits are
small compared with costs and inconvenience.
This study quantified the risks and
benefits of warfarin + aspirin vs
aspirin alone after acute coronary syndromes (ACS).
Conclusion: For patients with ACS who are at low or intermediate
risk of bleeding, benefits of warfarin outweigh risks
STUDY
1. MEDLINE search yielded
10 randomized trials (over 5900 patients; 11 000 patient-years) comparing 1) warfarin therapy (INR > 2.0) plus aspirin vs 2) aspirin
alone after ACS. No patient had received a stent.
2. The authors calculated
risks of bleeding from a validated Outpatient Bleeding Risk Index which
predicted risk of bleeding from warfarin based on 5 independent risk
factors: age over 65; history of stroke, history of GI bleeding, a specific co-morbid condition (eg, renal
insufficiency, severe anemia, recent myocardial infarction, and atrial
fibrillation). If three or more of these
factors are present, the risk of bleeding is high—30% in the first year. These
patients were excluded from the meta-analysis. For patients with 1 or 2 risk
factors risk of major bleeding is 7%; for patients with none, risk is 1%. These patients were included.
3. Many of the trial
patients had at least one risk factor for bleeding (MI) placing them in an
intermediate risk category.
RESULTS
1. Compared with aspirin alone, warfarin plus aspirin was associated
with a decrease in the risks.
2. Outcomes per 1000 patients per year:
Warfarin + aspirin Aspirin alone Absolute
difference NNT
MI 22 41 19 53
Ischemic stroke 4 8 4 250
Major bleeding 1.5 0.6 0.9 1100
Death No difference
DISCUSSION
1. The authors state
that, although the risk of major bleeding is increased with warfarin + aspirin
compared with aspirin alone (about 1 per 1000 per year in this meta-analysis),
the benefits outweigh the risks for many patients as long as patients with high
risk of bleeding from warfarin are excluded.
2. Benefits are greater
in the first 3 months. Nevertheless, the curves for the combined endpoints
continue to diverge for at least 5 years.
The length of therapy is a clinical judgment.
3. “On the basis of our
analysis, the benefits (of warfarin + aspirin vs aspirin
alone) should outweigh the harms for most patients.” Cardiovascular events
are usually more serious than bleeding events.
CONCLUSION
For patients with ACS at low or
intermediate risk for bleeding, the benefits of warfarin outweighed the risk of
bleeding.
Annals Int
Med August 16, 2005; 143: 241-50
Original investigation, meta-analysis. First author Michael B Rothberg,
===========================================================================
Describing a New Dog Vector for One of the Most Virulent Human Infections
Ever Identified.
8-6 ROCKY
MOUNTAIN SPOTTED FEVER – Changing Ecology And
Persisting Virulence
Rocky mountain
spotted fever (RMSF) is one of the
most virulent human infections ever identified. Up to 10% of persons infected
will die. Many more will require intensive care, and have sequellae such as
amputation and permanent learning impairment. This is despite the availability
of a simple and highly effective treatment (doxycycline).
Infections are sporadic, but
persistent. Only small proportions of vectors are infected.
RMSF occurs when Rickettsia rickettsii in the salivary glands of a vector tick is
transmitted into the human dermis, spreads, replicates in endothelial cells,
and elicits widespread vasculitis. Vascular permeability results,
leading to hypoperfusion and end-organ damage—most dangerous in the brain and
lung.
Diagnosis is difficult because of the
non-specific presentation of the disease. Symptoms include fever, headache,
myalgia, and (usually after 3 to 5 days) rash.
The rash evolves from macular to macro-papular, to petechial.
Organ-specific symptoms (nausea, vomiting, abdominal pain, and cough) confound
diagnosis by distracting attention from systemic manifestations. Serologic
analysis is not useful during an active infection.
Early clinical suspicion and
empirical therapy are essential. Severe illness and death are associated with a
delayed diagnosis, which may occur because of absence of a rash or presentation
during a season with a low level of tick activity.
In the
Other tick vectors, with specific
ecological features and hosts determine the prevalence and incidence of RMSF in
The disease may occur more frequently
than reported. Deaths from RMSF are at least 4 times the reported number.
Severe sequellae may be unreported.
“The reasons for the under-recognition of RMSF falls squarely on
physicians and the system that educates and reeducates them.” Far too few
physicians consider the diagnosis or take the time to inquire about tick bites
or exposures.
“No longer can we
consider RMSF a disease of only rural and southern venues; it has emerged and
re-emerged again. ”
NEJM August 11, 2005; 353:
551-53 “Perspective”, first author J
Stephen Dumler, Johns Hopkins University School of Medicine,
1 “Rocky Mountain Spotted Fever from an Unexpected Tick Vector
in
This study describes an outbreak of
RMSF in communities in rural eastern
The communities had large populations
of dogs. Dense populations of the brown dog tick were found feeding on dogs in
the yards of patients. Ticks were also found in crawl spaces under houses, in
discarded upholstered furniture, and in cracks in the stucco on the walls of
houses. Only the brown dog tick was found.
The brown dog tick (which differs
ecologically from the American dog tick) has not previously been reported to be
a natural vector for RMSF in the
The principle vectors of R rickettsii are the American dog tick
(eastern and central
1 The rash of RMSF commonly appears on
the distal areas of the extremities. Appearance on the palms and soles is often
described as a diagnostic feature. However, many cases occur without rash on
the palms and soles. Indeed, waiting for this sign may delay treatment. RTJ