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STATINS
Many Elders Don't Receive Primary Preventive Treatment for Cardiovascular Disease
Statins were unlikely to be prescribed for patients 75 or older.
Previous
research has shown that patients with known cardiovascular disease
(CVD) are less likely to receive these drugs as they get older, and
women are less likely than men to get these drugs. Whether the same is
true for primary prevention of CVD is unclear. In this cross-sectional
U.K. study, investigators assessed the effects of age and sex on primary
prevention of CVD in 37,000 patients (age,  40).
The proportion of patients who received antihypertensive drugs
increased with age from 5% among the youngest patients (age range,
40–44) to 57% among the oldest patients (age, 85).
In fact, the likelihood of receiving an antihypertensive drug
prescription increased significantly with each 5-year increment up to
age 84 but not for age 85.
The proportion of patients who received statins increased with age from
3% among the youngest patients (age range, 40–44) to 29% among patients
who were 70 to 74. The likelihood of receiving a statin drug
prescription increased significantly with each 5-year increment up to
age 74 but decreased significantly with each 5-year increment
thereafter. Treatment of women and men did not differ.
Comment: Increasing age increases risk for CVD, and many elders have high 10-year risk for CVD ( 20%). For some elders (age, 75),
primary prevention with antihypertensive and statin drugs can lower
this risk. However, fewer randomized trial data exist for this age group
(and especially for age 85)
than for age <75 75.="75." and="and" be="be" call="call" clarification="clarification" clinical="clinical" considered="considered" drugs="drugs" effects="effects" elders="elders" especially="especially" expectancy="expectancy" for="for" guidelines="guidelines" in="in" life="life" of="of" older="older" overall="overall" p="p" polypharmacy="polypharmacy" populations.="populations." researchers="researchers" should="should" than="than" the="the" these="these" those="those" trials="trials" using="using">
— Paul S. Mueller, MD, MPH, FACP
Published in Journal Watch General Medicine August 14, 2012
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statins primary prevention
Free
Full-Text Article
Summary
and Comment
Many Elders Don't Receive Primary Preventive Treatment for Cardiovascular
Disease
Statins were unlikely to be prescribed for patients 75 or
older.
Previous research has shown that patients with known
cardiovascular disease (CVD) are less likely to receive these drugs as they
get older, and women are less likely than men to get these drugs. Whether
the same is true for primary prevention of CVD is unclear. In this
cross-sectional U.K. study, investigators assessed the effects of age and
sex on primary prevention of CVD in 37,000 patients (age,
40).
The proportion of patients who received antihypertensive drugs increased
with age from 5% among the youngest patients (age range, 40–44) to
57% among the oldest patients (age,
85). In fact, the likelihood of receiving an antihypertensive
drug prescription increased significantly with each 5-year increment up to
age 84 but not for age
85.
The proportion of patients who received statins increased with age from 3%
among the youngest patients (age range, 40–44) to 29% among patients
who were 70 to 74. The likelihood of receiving a statin drug prescription
increased significantly with each 5-year increment up to age 74 but
decreased significantly with each 5-year increment thereafter. Treatment of
women and men did not differ.
Comment: Increasing age increases risk for CVD, and many elders
have high 10-year risk for CVD (
20%). For some elders (age,
75), primary prevention with antihypertensive and statin drugs
can lower this risk. However, fewer randomized trial data exist for this
age group (and especially for age
85) than for age <75 75.="75." and="and" be="be" call="call" clarification="clarification" clinical="clinical" considered="considered" drugs="drugs" effects="effects" elders="elders" especially="especially" expectancy="expectancy" for="for" guidelines="guidelines" in="in" life="life" of="of" older="older" overall="overall" p="p" polypharmacy="polypharmacy" populations.="populations." researchers="researchers" should="should" than="than" the="the" these="these" those="those" trials="trials" using="using">
— Paul
S. Mueller, MD, MPH, FACP
Published in Journal
Watch General Medicine August 14, 2012
Citation(s):
Sheppard
JP et al. Impact of age and sex on primary preventive treatment for
cardiovascular disease in the West Midlands, UK: Cross sectional study.
BMJ
2012 Jul 12; 345:e4535. (
http://dx.doi.org/10.1136/bmj.e4535)
statins
Impact of age and sex on primary preventive treatment for cardiovascular disease in the West Midlands, UK: cross sectional study
BMJ
2012;
345
doi: 10.1136/bmj.e4535
(Published 12 July 2012)
Cite this as:
BMJ
2012;345:e4535
More topics
- J P Sheppard, research fellow1,
- S Singh, clinical research fellow1,
- K Fletcher, research fellow1,
- R J McManus, professor2,
- J Mant, professor3
- Correspondence to: R J McManus richard.mcmanus@phc.ox.ac.uk
Abstract
Objectives
To establish the impact of age and sex on primary preventive treatment
for cardiovascular disease in a typical primary care population.
Design Cross sectional study of anonymised patient records.
Participants
All 41 250 records of patients aged ≥40 registered at 19 general
practices in the West Midlands, United Kingdom, were extracted and
analysed.
Main outcome measures
Patients’ demographics, risk factors for cardiovascular disease (blood
pressure, total cholesterol concentration), and prescriptions for
primary preventive drugs were extracted from patients’ records. Patients
were subdivided into five year age bands up to 85 (patients aged ≥85
were analysed as one group) and prescribing trends across the population
were assessed by estimating the proportion of patients prescribed with
antihypertensive drug or statin drug, or both, in each group.
Results
Of the 41 250 records screened in this study, 36 679 (89%) patients did
not have a history of cardiovascular disease and therefore could be
considered for primary preventive treatment. The proportion receiving
antihypertensive drugs increased with age (from 5% (378/6978) aged 40-44
to 57% (621/1092) aged ≥85) as did the proportion taking statins up to
the age of 74 (from 3% (201/6978) aged 40-44 to 29% (675/2367) aged
70-74). In those aged 75 and above, the odds of a receiving prescription
for a statin (relative to the 40-44 age group) decreased with every
five year increment in age (odds ratio 12.9 (95% confidence interval
10.8 to 15.3) at age 75-79 to 5.7 (4.6 to 7.2) at age ≥85; P<0 .001=".001" by="by" consistent="consistent" differences="differences" in="in" no="no" p="p" prescribing="prescribing" sex.="sex." there="there" trends="trends" were="were">
Conclusions
Previously described undertreatment of women in secondary prevention of
cardiovascular disease was not observed for primary prevention. Low use
of statins in older people highlights the need for a stronger evidence
base and clearer guidelines for people aged over 75.
dabigatran
SUMMARY
AND COMMENT
Within 12
weeks of marketing approval, dabigatran was found to be responsible for
more adverse events than nearly all other medications.
Reviewing:
Radecki RP. Ann Intern Med 2012 Jul 3; 157:66
ACE-inhibitor
Free
Full-Text Article
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Summary
and Comment
ACE Inhibitor Use Lowers Risks for Pneumonia
A meta-analysis showed that
angiotensin-converting–enzyme inhibitors, but not
angiotensin-receptor blockers, lowered risk.
Many
patients (as many as one third) who take
angiotensin-converting–enzyme (ACE) inhibitors develop coughs.
However, an enhanced cough reflex might lower risk for pneumonia. In this
meta-analysis of 37 studies (18 randomized trials, 11 cohort studies, and 8
case-control studies), investigators evaluated the association between use
of ACE inhibitors or angiotensin-receptor blockers (ARBs) and risk for
pneumonia.
Overall, use of ACE inhibitors was associated with a significant 34%
lower risk for pneumonia compared with no use of ACE inhibitors and a
significant 30% lower risk for pneumonia compared with ARB use. Subgroup
analyses of patients with stroke or heart failure yielded similar results.
Finally, use of ACE inhibitors compared with no use was associated with a
significant 27% lower risk for pneumonia-related death.
Comment: In this study, ACE inhibitor use was associated with
attenuation of risks for pneumonia and pneumonia-related death. The authors
suggest that "patients taking ACE inhibitors who develop cough should,
providing that cough is tolerable, persist with treatment." Although this
suggestion is reasonable (especially because ACE inhibitors confer
considerable cardiovascular benefit), many patients with ACE
inhibitor–related cough find this side effect too annoying or
disruptive to continue taking the drug.
— Paul
S. Mueller, MD, MPH, FACP
Published in Journal
Watch General Medicine August 2, 2012
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atrium fibrilleren AF
rate controle = hartfrequentie
Rhythm controle = ritme
Detail van boezemfibrilleren met een snelle ventrikel-respons
Boezemfibrilleren is een ritmestoornis waarbij er sprake is van een
chaotische depolarisatie van de atria. De sinusknoop wordt hierdoor als
het ware overschreeuwd. De electrische acitiviteit in de boezems kan tot
600 / min oplopen. Boezemfibrilleren ontstaat vaak rond eilandjes van
cellen rond de inmonding van de longvenen in het linker atrium.
Boezemfibrilleren is een van de meest voorkomende ritmestoornissen. Ongeveer 10% van de 70 jarige heeft boezemfibrilleren
[1].
De kans op boezemfibrilleren is verhoogd bij gedilateerde atria,
atriale ischemie, hyperthyreoidie en alcoholgebruik. Er bestaan ook
zeldzame erfelijke vormen van boezemfibrilleren.
De AV knoop is te traag om elk signaal uit de boezems door te
geven. Willekeurig wordt er wel een signaal doorgegeven dat leidt tot
kamercontractie. Door deze willekeur zijn de ventriculaire slagen
onregelmatig en dat is meteen ook een van de belangrijkste ECG-kenmerken van boezemfibrilleren.
Soms is er sprake van grofslagig boezemfibrilleren dat zich uit
in een onregelmatige basislijn, soms is de basislijn volledig vlak.
Boezemfibrilleren wordt als volgt ingedeeld:
- Eerste geregistreerde episode: indien boezemfibrilleren voor het eerst geregistreerd wordt.
- Recidiverend boezemfibrilleren: na twee of meer episodes.
- Paroxysmaal boezemfibrilleren: als recidiverend boezemfibrilleren telkens spontaan over gaat in sinusritme.
- Persisterend boezemfibrilleren: indien een episode van boezemfibrilleren langer dan 7 dagen aanhoudt.
- Permanent boezemfibrilleren: indien boezemfibrilleren aanhoudt ondanks een poging tot medicamenteuze of electrische cardioversie
Lone AF is boezemfibrilleren in patienten jonger dan 60 jaar
zonder klinische of electrocardiografische aanwijzingen voor hart- en of
longziekte. Deze patiënten hebben een gunstigere prognose ten aanzien
van trombo-embolische events.
Non-valvulair boezemfibrilleren is boezemfibrilleren
zonder aanwijzingen voor rheumatische hartklepziekte of bij patienten
zonder mechanische hartklep of hartklep reparatie.
[2]
De behandeling van boezemfibrilleren kan door middel van
ritme-controle (rhythm-control) of frequentie-controle (rate-control).
Er is veel onderzoek gedaan naar de beste strategie. De verschillen op
de lange termijn tussen beide strategieën verschillen in grote groepen
patiënten weinig.
[3]
- Bij rhythm-control wordt er gestreefd naar sinusritme door met medicatie of electrische cardioversie het boezemfibrilleren te beëindigen.
- Bij rate-conrol wordt het boezemfibrilleren
geaccepteerd. Hierbij is de behandelig gericht op het voorkomen van hoge
hartfrequenties door de AV knoop te onderdrukken met medicijnen. De
streeffrequentie is onder de 100 slagen / min in rust en liefst nog iets
lager.
atrial fibrillation AF
Rhythm vs. Rate Control in Older Atrial Fibrillation Patients
Rhythm control might be superior in the long term.
In a major trial published in 2002 (AFFIRM;
JW Gen Med Dec 13 2002),
investigators found no difference in outcome between rhythm and rate
control during 5 years of follow-up in patients with atrial fibrillation
(AF). However, many clinicians still favor rhythm control. In this
retrospective cohort study, researchers used a Canadian database to
identify 26,000 hospitalized patients (median age, 77) with incident AF
who were treated with rhythm or rate control. Patient follow-up was
available for as long as 9 years (median, 3.1 years); during that time,
half of the patients died.
Analyses were adjusted for many demographic and clinical confounders.
Compared with rate control, rhythm control was associated with 7%
higher mortality at 6 months, equal mortality through 4 years, and 11%
and 23% lower mortality at years 5 and 8, respectively.
Comment: Results from this population-based older cohort are
similar to those of AFFIRM — no difference between rhythm and rate
control for AF during short-term and intermediate-term follow-up. In the
current analysis, however, rhythm control was superior during longer
follow-up. Because potential unidentified confounders can't be ruled out
in a retrospective study, a long-term randomized trial would be
justified to confirm these findings.
— Thomas L. Schwenk, MD
Published in Journal Watch General Medicine July 26, 2012
Citation(s):
PPI C. difficile
Summary
and Comment
Proton-Pump Inhibitors Raise Risk for C. difficile Infections
In two
meta-analyses, PPI use was associated with a 1.7-fold higher risk for
Clostridium difficile infection.
In February 2012, the FDA
issued a
safety
alert regarding an association between proton-pump inhibitors (PPIs)
and
Clostridium difficile infection. In new meta-analyses, two
groups of researchers used slightly different criteria to select studies in
which this association could be evaluated; all included studies (23 and 42,
respectively) were observational (cohort or case-control). Each
meta-analysis involved roughly 300,000 patients.
In both meta-analyses, risk for
C. difficile infection was
significantly higher in PPI users than in nonusers (risk ratio, about 1.7).
Although results across individual studies were heterogeneous, nearly all
trended toward higher risk. Most of the included studies were adjusted for
confounding variables, including antibiotic use. Concomitant use of both
PPIs and antibiotics — examined in one meta-analysis — was
associated with greater risk for
C. difficile infection than was use
of PPIs alone or antibiotics alone. Risk for
C. difficile infection
was higher with histamine (H)
2-receptor antagonists than with no
acid-suppressive therapy, but lower with H
2-receptor antagonists
than with PPIs.
Comment: The opportunity for residual confounding in these
studies is substantial, because sicker patients are more likely both to
receive PPIs and to be vulnerable to
C. difficile infection. Still,
these worrisome findings should remind clinicians to initiate PPIs only for
valid indications and to stop PPIs in patients who take them for unclear
reasons.
— Allan
S. Brett, MD
Published in Journal
Watch General Medicine July 31, 2012
statines
Should Anyone Not Take a Statin?
In a meta-analysis, benefits of statins outweighed risks, even in the healthiest patients.
Meta-analyses have shown
that statins safely lower the incidence of major vascular events (MVEs,
including nonfatal myocardial infarction or coronary death, any stroke,
or coronary revascularization) by about 20% for every 40 mg/dL reduction
in LDL cholesterol level. But the net benefit of statin therapy in
patients at low vascular risk has been unclear.
In a new meta-analysis of patient-level data from 27 randomized
trials of statins versus control treatments or high- versus low-dose
statins, researchers stratified 170,000 participants by their pretrial
5-year risk for MVEs (from <5% to
30%).
Overall, statins lowered 5-year relative risk for MVEs by 21% per 40
mg/dL reduction in LDL cholesterol level, and risk reductions were more
pronounced in the lowest risk categories (as much as 38% per 40 mg/dL
reduction in LDL cholesterol level for participants with 5-year vascular
risk <5%). Similar relative risk reductions occurred when patients
with prior vascular disease, diabetes, or chronic kidney disease were
excluded. Statins lowered 5-year relative risk for vascular death by at
least 12% and did not raise risk for nonvascular death in patients with
or without histories of vascular disease.
Comment: Among patients with 5-year MVE risk of <10%,
statins lowered the absolute 5-year MVE risk by about 11 events per 1000
patients for each 40 mg/dL of reduction in LDL cholesterol level. This
benefit substantially outweighs any known risk of statin therapy. The
authors and editorialists suggest that current guidelines, which
generally do not recommend statin therapy for low-risk patients, should
be reevaluated. However, lingering questions include the following: In
the general population, are statins tolerated as well as was reported in
the randomized trials? Among the lowest-risk patients in real-life
practice, is the long-term balance of benefits and harms as favorable as
predicted from the trials? And, if low-risk patients choose to take
statins, what are the appropriate ages to start and stop?
— Bruce Soloway, MD
Published in Journal Watch General Medicine June 12, 2012
Citation(s):
Cholesterol Treatment Trialists'
(CTT) Collaborators. The effects of lowering LDL cholesterol with statin
therapy in people at low risk of vascular disease: Meta-analysis of
individual data from 27 randomised trials.
Lancet 2012 May 17; [e-pub ahead of print]. (
http://viajwat.ch/KqxJye)
CRP as a Predictor of Statin Efficacy: Time to Move On?
An Interview With Peter S. Sever, MB BChir, PhD
statins
The Study
Sever PS, Poulter NR, Chang CL, et al; ASCOT
Investigators. Evaluation of C-reactive protein prior to and
on-treatment as a predictor of benefit from atorvastatin: observations
from the Anglo-Scandinavian Cardiac Outcomes Trial.
Eur Heart J. 2012;33:486-494.
About the Interviewee
Peter S. Sever, MB BChir, PhD, is Professor
of Clinical Pharmacology and Therapeutics at Imperial College London;
Honorary Consultant Physician at the Imperial Healthcare NHS Trust; and
Co-director of the International Centre for Circulatory Health, London,
United Kingdom. During the past decade, he established a major research
program in the pathogenesis and treatment of cardiovascular disease. He
is joint editor-in-chief of
Journal of the Renin-Angiotensin-Aldosterone System and has been a member of the editorial boards of several journals, including
Journal of Hypertension,
Journal of Human Hypertension, and
Clinical Science.
Professor Sever is past president of the British Hypertension Society
(1989-1991) and past president of the European Council for Blood
Pressure and Cardiovascular Research. He is also a Fellow of the
European Society of Cardiology and past Chairman of the Fellowships
Committee of the British Heart Foundation.
His current research interests include all aspects of cardiovascular
disease, including the pathophysiology of vascular disease, the
evaluation of antihypertensive drug therapy, and multiple risk factor
intervention in hypertensive populations. He is also interested in the
epidemiology of hypertension, with particular reference to environmental
influences on blood pressure and ethnic differences. Professor Sever
was co-chair, along with Björn Dahlöf, MD (Sahlgrenska University
Hospital, Göteborg, Sweden), of the Anglo-Scandinavian Cardiac Outcomes
Trial (ASCOT) executive committee.
STATINS
Oxford, UK - New data from an individual patient meta-analysis of
27 large statin trials shows that statin treatment is clearly
beneficial in much lower-risk patients than are currently recommended
for such therapy in most guidelines [
1].
And authors of an accompanying comment suggest
that with this new data, everyone over 50 should now be eligible for
statin treatment.
The meta-analysis, published online May 16, 2012 in the Lancet, was conducted by the Cholesterol Treatment Trialists' (CTT) Collaborators.
They analyzed data from 175 000 individuals and grouped participants
into five baseline categories of cardiovascular risk. Outcomes were
studied in trials comparing statin with no statin treatment and of more
vs less intensive statin regimens.
Results showed that statins reduced the risk
of serious vascular events by around 21% for each 1-mmol/L reduction in
LDL cholesterol in each of the five baseline risk groups, including
those people with the lowest risk of vascular disease.
Benefits greatly exceeded harms
One of the senior authors on the paper,
Prof Colin Baigent (Clinical Trial Service Unit, Oxford, UK), commented to
heartwire: "Last year Cochrane published
a review of statins in primary prevention
that was somewhat unclear in its conclusions. They showed that although
there was a clear reduction in mortality with statins, they were
uncertain about adverse effects. We wanted to clarify the situation, so
we looked at all the available individual patient data from all trials
that included low-risk patients. As well as all the primary-prevention
trials, these include some trials where both primary- and
secondary-prevention patients were included, such as the
Heart Protection Study. This was a much more thorough analysis than the Cochrane review, which only had access to the overall trial results."
Baigent continued: "We found the relative
reduction in risk of cardiovascular events with a statin is just as good
in the lowest-risk group as in higher-risk groups. Even in the very
lowest-risk group studied (those with a risk below 10% in 10 years), the
benefits greatly exceeded the harms."
Primary prevention is obviously needed.
"Half of cardiac deaths happen in people who
have not previously had heart disease, so there is a limit to what can
be achieved just with secondary prevention. So primary prevention is
obviously needed. The question is where we set the threshold. And our
data suggest this should be lowered to a risk of 10% over 10 years."
Baigent believes the decision on whether to
take a statin needs to be made on the basis of risk of the patient
rather than on their cholesterol level. "Typically, at the moment, the
public and many doctors think that statins are necessary only if a
patient has high cholesterol. But the preferable view would be that a
statin is needed if you are at any increased risk of heart disease."
A statin is needed if you are at any increased risk of heart disease.
He added that everyone is supposed to have a
vascular check in middle age, and the current recommendation in the UK
is that if they are found to have a risk of a cardiovascular event of
more than 20% over 10 years they should be offered a statin. "But we
found in this current meta-analysis that the benefits of statins are
still obvious at a risk level of 10% over 10 years, and even below
that."
At present in the UK, five million patients
take statins, and another five million are eligible to take them but are
not receiving them, Baigent reported. "If the threshold were reduced to
a cardiac risk of 10% over 10 years, an additional five million people
would be eligible to receive these drugs. Simvastatin is off patent and atorvastatin
is now coming off patent, so this will not be an expensive exercise. It
is right and proper that there is an assessment of safety, but we have
now done that and shown the benefits to greatly outweigh the risks. If
the threshold were lowered to 10%, we could avoid 10 000 events,
including 2000 deaths every year."
If the threshold was lowered to 10%, we could avoid 10 000 events, including 2000 deaths every year.
Asked if everyone should just receive a statin
at a certain age, Baigent said this was one possibility. "It is up to
the guidelines committees to decide on the strategy. We have called for NICE
to reconsider the threshold they recommend for statin treatment. All we
are saying is that we should at least treat everyone with a risk of 10%
or more over 10 years. But we actually showed benefit in patients with a
lower risk than this. People can be educated about risk. Everybody
knows their age and if they are overweight, smoke, or don't exercise
enough. It's not difficult to find out your cholesterol, blood
pressure, family history, or whether you are diabetic. These things then
should then trigger the thought that you might be able to benefit from a
statin."
Statins for everyone over 50?
In the comment article, Drs Shah Ebrahim and Juan P Casas
(London School of Hygiene and Tropical Medicine, UK) suggest that as
most people older than 50 years are likely to be at a >10% 10-year
risk of a cardiovascular event, it would be more pragmatic to use age as
the only indicator for statin prescription, which would avoid the costs
of vascular screening checks.
Major results for the new meta-analysis showed
that statin treatment reduced the risk of major vascular events by 21%
per 1.0-mmol/L reduction in LDL, and this was largely irrespective of
age, sex, baseline LDL cholesterol, previous vascular disease, and
baseline cardiovascular risk. The proportional reduction in major
vascular events was at least as big in the two lowest-risk categories as
in the higher-risk categories.
Risk reduction in major vascular events statin treatment according to baseline risk
Baseline risk (risk of CV event over five years), %
|
Risk reduction (95% CI) per 1-mmol LDL reduction
|
<5
|
0.57 (0.36-0·89)
|
5-10
|
0.61 (0.50-0·74)
|
10-20
|
0.77 (0.69-0·85)
|
20-30
|
0.77 (0.71-0·83)
|
20-30
|
0.78 (0.72-0·84)
|
Overall
|
0.76 (0.73-0·79)
|
5% risk over five years=10% risk over 10 years
There was no evidence that reduction of LDL
cholesterol with a statin increased cancer incidence (RR per 1.0-mmol/L
LDL-cholesterol reduction 1.00, 95% CI 0.96-1.04), cancer mortality (RR
0.99, 95% CI 0.93-1.06), or other nonvascular mortality.
What about side effects?
In terms of side effects, the data show that
there was a small increased risk of myopathy (excess incidence of about
0.5 per 1000 over five years) and rhabdomyolysis (excess incidence of
about 0.1 per 1000 over five years). There was also an increase of
hemorrhagic strokes per 1.0-mmol/L LDL-cholesterol reduction of about
0.5 per 1000 people treated over five years. But the authors write that
"this was outweighed by the reduction in ischemic stroke (as well as the
reduction in other occlusive vascular events and deaths) even in
individuals whose five-year risk of major vascular events is lower than
5%."
They also report an absolute excess of
diabetes associated with statin treatment of about 0.1% per year. But
they estimate that the increased risk of cardiovascular events
associated with this excess in diabetes is more than 50 times smaller
than the absolute benefit observed with statin therapy in low-risk
patients.
biphosphanate foamax alendroinezuur
Mixed results from trials of extended bisphosphonate treatment leave treatment and monitoring guidelines uncertain.
Reviewing: Whitaker M et al. N Engl J Med 2012 May 31; 366:2048
Black DM et al. N Engl J Med 2012 May 31; 366:2051
Free Full-Text Article
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Summary and Comment
Bisphosphonate Use Raises Risk for Atypical Femoral Fracture
But absolute risk was still small.
Bisphosphonate
use may have a paradoxical effect of adversely affecting bone
architecture, thereby raising risk for atypical femoral fractures. In
this retrospective Swiss case-control study, researchers explored this
relation using data from a single trauma center that captured 95% of all
femoral fractures in Geneva. Between 1999 and 2009, 477 patients with
subtrochanteric or femoral shaft fractures were identified; 39 had
atypical fractures (defined as a transverse or short oblique fracture
rather than a typical oblique intertrochanteric or shaft fracture).
Of those 39 patients with atypical fractures, 82.1% were using
bisphosphonates, compared with 6.4% of those with classic femoral
fractures (odds ratio, 67) and 11.5% in a control group without fracture
(OR, 35). Adjustment for age, sex, and use of vitamin D,
corticosteroids, and proton-pump inhibitors did not change the odds
ratio for atypical versus classic fracture. Risk also rose with longer
duration of bisphosphonate use; for example, the odds ratio for atypical
fracture compared to classic fracture was 117 with 5 to 9 years of use
and 176 for longer than 9 years.
Comment: Bisphosphonate use appears to confer a large
relative, albeit very small absolute, risk for atypical femoral
fracture, particularly when used for 5 years or more. Concern about
atypical fractures and other adverse effects has prompted some experts
to recommend discontinuation of bisphosphonates in low-risk patients
after several years, but this decision requires a detailed discussion of
the risks and benefits –– particularly about balancing an elevated risk
for vertebral fractures (after stopping the drug) against the small
absolute risk for atypical femoral fractures (if the drug is continued).
— Thomas L. Schwenk, MD
Published in Journal Watch General Medicine June 7, 2012
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DEPRESSION
on line 31-5-2012
Hello. This is Dr. Scott Irwin, Chief of
Psychiatry and Psychosocial Services at San Diego Hospice and The
Institute for Palliative Medicine. I'd like to talk to you about the
rapid treatment of depression in patients who don't have time to wait
for standard antidepressant therapy to work.
Depression is not a normal part of end
of life. Only 15% of patients in hospice and palliative care settings
have major depressive episodes. These episodes are treatable, and if we
don't treat them, depression causes a tremendous amount of suffering --
not only for the patient but for families as well.
The way we treat depression [at the end of
life] is with psychostimulants. We often use methylphenidate, and we'll
start by giving 5 mg in the morning. If, in an hour, the patient hasn't
had any effects that they don't like, we'll give them another dose 4
hours later. As long as we are continuing to get benefit and no side
effects, we'll continue to increase the dose; so the next day, we might
go to 10 mg and 10 mg [later in the day], and the day after that, 15 mg
and 15 mg [in a second daily dose]. We rarely see doses effective over
20 mg twice a day. In the home setting, we might go a little slower and
increase the dose every 5-7 days instead.
We see very few side effects. We don't see tolerance, and you might actually get some adjunct analgesia as well.
So, if you have somebody who's depressed and
they don't have time to wait for standard antidepressant therapies to
work, think of using psychostimulants and titrate them effectively,
safely, and rapidly. Be sure to treat depression so that we can relieve
suffering in both patients and their families.
Thank you for listening. This is Dr. Scott
Irwin, Chief of Psychiatry and Psychosocial Services at San Diego
Hospice and The Institute for Palliative Medicine.
Warfarin Ineffective for HF Without Atrial Fibrillation
In the WARCEF trial, reduced stroke rates were offset by increased bleeding.
The benefits of chronic
anticoagulation in patients with heart failure (HF) who do not have
atrial fibrillation are controversial. Previous clinical trials were
underpowered to generate conclusive evidence, and results of
observational studies have conflicted.
In the international WARCEF trial, investigators compared warfarin
with aspirin in 2305 patients without a contraindication to
anticoagulation (mean age, 61; 80% men). All were in sinus rhythm and
had systolic left ventricular ejection fractions less than 35% (mean,
25%). Patients were randomized to receive warfarin (target international
normalized ratio [INR], 2.0–3.5; mean, 2.5) or aspirin (325 mg) daily.
Sites received sham INR results for patients in the aspirin group.
At a mean follow-up of 3.5 years, the rate of the primary endpoint of
ischemic stroke, intracerebral hemorrhage, or all-cause death did not
differ significantly between the warfarin and aspirin groups (7.47 and
7.93 per 100 patient-years, respectively). Rates of ischemic stroke were
significantly lower with warfarin than with aspirin (0.72 vs. 1.36 per
100 patient-years), but rates of major hemorrhage were twice as high
(1.78 vs. 0.87 per 100 patient-years). During follow-up, patients in the
warfarin group were within the target INR range 63% of the time.
Comment: WARCEF showed no net benefit of warfarin in patients
in sinus rhythm with systolic heart failure. Up to now, in the absence
of evidence, the use of anticoagulation in this patient population has
presumably depended on the instincts of the treating clinician. This
well-designed clinical trial injects much-needed evidence into the
decision; however, whether clinicians will change their practices based
on the results remains to be seen. Furthermore, we don't know whether
newer agents, which may provide more reliable anticoagulation than
warfarin, might be beneficial in this context.
— Frederick A. Masoudi, MD, MSPH, FACC, FAHA
Published in Journal Watch Cardiology May 9, 2012
multiple myeloom
25-04-2012
Interim
results from a Phase I/II clinical study suggesting that a single
vaccine can treat myeloma and other cancers has generated a deluge of
interest in the popular press recently.
Last week, several newspapers published articles about a therapeutic
vaccine that has the potential to train the body’s immune system to seek
out and destroy myeloma cells. These stories were based on a press
release issued by the Israeli biotechnology company, Vaxil
Biotherapeutics.
The vaccine, known as ImMucin, targets a protein called MUC-1 found
in abundance on the surface of 90% of cancer cells including myeloma
cells. When the vaccine is injected into the patient’s body, it
stimulates an immune response which identifies and removes cancer cells
which express MUC-1.
ImMucin is currently being investigated in a Phase I/II study in
myeloma patients in Israel. Of the ten patients recruited to date, seven
have successfully completed treatment. Although the results have not
yet been published in a recognised peer-reviewed medical journal, the
press release stated that ImMucin generated a robust and specific immune
response after 2 - 4 doses out of a maximum of 12 doses in all patients
with no side-effects.
Importantly, the vaccine showed signs of clinical efficacy, with some
patients demonstrating a reduction in their myeloma one month after
completing treatment; three patients showed a complete response (no
detectable paraprotein).
While ImMucin appears to be safe and the initial results in myeloma
patients promising, it remains too preliminary to conclude that the
vaccine is an effective treatment for myeloma or any other cancer.
More work with a much larger number of patients will need to be
carried out and followed-up for a longer period of time to prove that
ImMucin is safe and effective in myeloma patients.
About MUC-1:
MUC-1 belongs to a family of sugar-coated proteins
called mucins found in normal cells such as those lining the surface of
organs including the lung, stomach, intestines and eyes. Mucins protect
the body from infection by preventing pathogens such as bacteria and
viruses from reaching the cell surface.
Excessive amounts of MUC-1 are associated with different types of
cancer. However, in cancer cells, the sugar make up of MUC-1 is
different to that on normal cells. This means that MUC-1 on cancer cells
can be targeted without affecting normal cells.
About vaccines:
A vaccine is a biological preparation which improves
the immune system’s natural ability to protect the body against disease
caused by “foreign agents”. Originally, vaccines were developed to
protect the body against infectious microbes. The vaccine itself is made
up of a harmless version of the microbe that does not cause disease but
stimulates an immune response against the microbe. More recently,
cancer vaccines have been developed to prevent or treat existing
cancers; usually a protein that is unique to the cancer is used as the
target for the immune system to act on.
ImMucin is one of many MUC-1 based cancer vaccines currently being
tested in myeloma and other cancers in over 30 clinical studies
worldwide.
About the ImMucin study:
The ImMucin study is being conducted by Vaxil
Biotherapeutics at the Hadassah Medical Center, Jerusalem, Israel. A
Phase I/II study is currently ongoing, with a total of 15 myeloma
patients expected to enrol. There is no information as yet if the study
will open elsewhere in the world.
Aspirin to Prevent Cancer
The Story Continues to Evolve
Bruce Soloway, MD
Posted: 05/21/2012; Journal Watch © 2012 Massachusetts Medical Society
Abstract and Introduction
Abstract
Daily aspirin reduced short-term risk for cancer incidence and death, and also lowered risk for metastasis.
Introduction
Previous meta-analyses of long-term follow-up
data from five large randomized trials of daily aspirin for prevention
of vascular events showed that, compared with placebo or no treatment,
aspirin lowered colon cancer incidence and mortality after 8 to 10 years
and lowered mortality from other common solid cancers after 5 to 15
years (JW Gen Med Dec 29 2011). Now, these investigators have conducted
two new meta-analyses of trials of aspirin for preventing vascular
events: One, designed to assess the short-term effects of aspirin on
cancer incidence and mortality, included in-trial data from 51 studies
that involved more than 77,000 patients — and the other, aimed at
studying aspirin's effects on risk for metastasis, included data from
five U.K. studies that involved more than 17,000 patients.
In the first analysis, 34 trials in which
cancer deaths were reported showed that significantly fewer such deaths
occurred among patients who received aspirin (odds ratio, 0.85); this
benefit was most pronounced ≥5 years after randomization (OR, 0.63). In
six primary-prevention trials, cancer incidence was significantly lower
for patients who received aspirin (OR, 0.88), and this benefit was
apparent after 3 years of follow-up. Meanwhile, aspirin's prevention of
vascular events and its association with extracranial bleeds both waned,
becoming nonsignificant after 3 years.
Aspirin's observed benefits after 3 to 5
years of follow-up suggest that it might inhibit metastasis, not just
initial carcinogenesis. In the second meta-analysis, the investigators
assessed time to diagnosis of solid cancers and identification of
metastases. Aspirin slightly lowered the overall incidence of cancer;
moreover, compared with cancers in the control group, more cancers in
the aspirin group remained localized (OR, 1.24), whereas fewer cancers
metastasized (OR, 0.64). Among patients who developed incident solid
cancers, those taking aspirin were significantly less likely to have
metastases at diagnosis or follow-up (OR, 0.59). This effect was
significant only for colorectal cancers (OR, 0.36) and all
adenocarcinomas (OR, 0.52). Among patients with initial diagnoses of
localized cancer, those taking aspirin had significantly lower risk for
subsequent metastasis (hazard ratio, 0.45) and better survival rates
(HRs, 0.71 for cancer-related deaths and 0.81 for all-cause deaths).
Safety of Statins
An Update
Miao Hu, PhD; Bernard M.Y. Cheung, PhD, FRCP; Brian Tomlinson, MD, FRCP
Posted: 05/22/2012; Ther Adv in Drug Safe. 2012;3(3):133-144. © 2012 Sage Publications, Inc.
Abstract and Introduction
Abstract
Statins are widely used and have been proven
to be effective in the prevention of atherosclerotic vascular disease
events, primarily by reducing plasma low-density lipoprotein cholesterol
concentrations. Although statins are generally well tolerated and
present an excellent safety profile, adverse effects from muscle
toxicity and liver enzyme abnormalities may occur in some patients.
Myopathy and rhabdomyolysis are rare with statin monotherapy at the
approved dose ranges, but the risk increases with use of higher doses,
interacting drugs and genetic predisposition. Asymptomatic increases in
liver transaminases with statin treatment do not seem to be associated
with an increased risk of liver disease. Therefore, statin treatment can
be safely used in patients with mild to moderately abnormal liver tests
that are potentially attributable to nonalcoholic fatty liver disease
and can improve liver tests and reduce cardiovascular morbidity in this
group of patients. The risks of other unfavorable effects such as the
slightly increased risk of new-onset diabetes and potentially increased
risk of haemorrhagic stroke are much smaller than the cardiovascular
benefits with the use of statins.
Aspirin Prevents Recurrent Unprovoked Venous Thromboembolism
Aspirin is probably less effective –– but safer –– than warfarin.
Patients with unprovoked
venous thromboembolism (VTE) face a dilemma: Recurrent VTE is common
after warfarin anticoagulation is stopped, but the cumulative incidence
of serious bleeding is high when patients continue warfarin therapy
indefinitely. This difficult tradeoff provides an impetus to see whether
aspirin is a suitable alternative for such patients.
Italian researchers identified 403 patients with a first symptomatic
VTE event that was unprovoked (i.e., not associated with standard VTE
risk factors); 63% had proximal deep venous thrombosis, and 37% had
pulmonary embolism. After 6 to 18 months of treatment with a vitamin K
antagonist, patients were randomized to either aspirin (100 mg daily) or
placebo for 2 years.
The incidence of recurrent VTE was significantly lower in the aspirin group than in the placebo group (6.6% vs. 11.2% annually;
P=0.02).
The frequency of bleeding events was identical in the two groups (1
major bleed and 3 nonmajor bleeds). Aspirin afforded protection both to
patients whose index event was deep venous thrombosis and to those whose
index event was pulmonary embolism.
Comment: For patients with unprovoked VTE, this trial provides
persuasive evidence that aspirin reduces the incidence of recurrent
events after conventional warfarin therapy. Aspirin is less effective
than warfarin, but bleeding risks are lower with aspirin. Newer oral
anticoagulants (e.g., dabigatran and rivaroxaban) have also been studied
as extended maintenance therapies for patients with VTE, but are not
yet FDA-approved for this purpose.
— Allan S. Brett, MD
Published in Journal Watch General Medicine May 24, 2012
Henry R. Black, MD: Hi. I'm Dr. Henry Black, Clinical Professor of Internal Medicine at the New York University School of Medicine and a member of the Center for the Prevention of Cardiovascular Disease at that institution. I am also Immediate Past President of the American Society of Hypertension. I'm here with my colleague and friend, Bob Morrow.
Robert W. Morrow, MD: Thanks, Henry. I'm Bob Morrow, Associate Professor of Family and Social Medicine at the Albert Einstein College of Medicine. I have been in general family practice for 30 some-odd years -- mostly odd years. That's why we call it the borderline medical practice. I am also the Associate Director of Interventional Continuing Medical Education at the Center for Continuing Medical Education at Albert Einstein College of Medicine.
The question I'm posing to you is one that has been puzzling to me. Having been brought up in the generation before calcium channel blockers (CCBs) got their big push as the expensive new guys on the block that weren't any better, I'm used to sticking with beta-blockers, thiazides, and angiotensin-converting enzyme (ACE) inhibitors before going to CCBs as the second- or third-line drug, particularly in diabetic patients. Now we have a resurgence of the use of amlodipine. This is a drug that, in a good number of my patients, makes ankles swell. One of the reasons we treat blood pressure is to prevent heart failure and to prevent renal failure. Where does amlodipine fit in with all of that?
Dr. Black: Excellent question, and one that involves a little history. The first CCB or calcium antagonist was released in 1967, and it was verapamil. Over the years, CCBs have been lumped together because they block the entry of calcium into cells. In fact, every antihypertensive drug does that, directly or indirectly. We ought to view calcium antagonists as existing in 2 different flavors: non-dihydropyridines such as verapamil and diltiazem, and dihydropyridines, which are just about everything else. Verapamil and diltiazem slow heart rate, maybe improve insulin sensitivity, are not diabetogenic, and are pretty much metabolically neutral.
Dihydropyridines came along later, and they are very powerful antihypertensive drugs. In fact, amlodipine was originally in a study [in which it was administered at] 2.5 mg to 20 mg. At 20 mg, edema is invariable, so only 2.5 mg, 5 mg, and 10 mg are now currently available, but someone could take 2 if they wished. This is especially an issue for women, but not so much for men. I rarely go beyond 5 mg, but for women, I will often go to 10 mg.
Amlodipine has been the comparator drug in a large number of studies, including the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) and the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT). Amlodipine does very well when it comes to preventing problems, but it seems to cause heart failure, reasonably commonly. If a patient has heart failure, clearly you are not going to be using amlodipine. In the ALLHAT study, when it came to any number of issues, especially for stroke prevention, amlodipine was almost as good as chlorthalidone was.
The British recently stated in their National Institute for Clinical Excellence (NICE) guidelines that, for individuals over 55 years of age or of any age if of African or Caribbean descent, either a thiazide-like diuretic or a CCB is the first drug of choice, and the second drug is an ACE inhibitor or an angiotensin receptor blocker, with a diuretic after that. The NICE group's recommendation is probably the most evidence-based that we can see. They have the ability to look at enormous numbers of records through the National Health Service in Britain, and they have the ability to look at billions of bits of data, and that was their recommendation.
Amlodipine is an excellent drug for preventing strokes. In ALLHAT, glomerular filtration rates went up a little bit and stayed there, but people with renal disease didn't do worse. In the African American Study of Kidney Disease and Hypertension (AASK) study, which compared amlodipine with metoprolol and ramipril, patients did fine on amlodipine if they did not have proteinuria. If they did have proteinuria with amlodipine, they stopped the treatment. Therefore, when somebody asks what I would give to a patient, what my first-choice drug would be, my question is always, "Tell me about the patient."
Dr. Morrow: Exactly.
Dr. Black: If the patient is an older African American who does not have heart failure or who might have angina or something else that a CCB would help, that's one thing. If the patient is a young, white individual who is asymptomatic, I'm not going to pick something like [amlodipine]. I think that's how we should approach each case.
Dr. Morrow: The New York State Medicaid Program's take on this, particularly the analytics from the State University of New York, is that we can't really distinguish between races. In some studies, race may have been poorly controlled. Also, you can't look at a person's degree of melanin and say that he is of this race, that race, or some other race. It becomes complex, and they don't suggest that you use it for your decision-making. I tend to agree with that. I will say that I frequently get into more trouble practically than I expect with the drug in terms of edema and development of what appears to be a decreased ejection fraction. I'm not convinced that it has a renal-protective mechanism that you would see over many years with an ACE inhibitor. Even knowing this new stuff, I tend to use amlodipine as number 3, and it would be good if we had more guidance from a national guideline. Do you know what is holding that up, or should we talk about that next time?
Dr. Black: We can talk about that next time. Thanks very much.
