Computed tomography angiography (CTA) is an effective tool to
determine the presence and severity of peripheral arterial disease
(PAD) in patients with intermittent claudication, according to the
results of a systematic review and meta-analysis reported in the
January 28 issue of the Journal of the American Medical Association.

"...CTA is an increasingly attractive imaging modality for assessing
lower extremity...PAD," write Rosemarie Met, MD, from Academic
Medical Center in Amsterdam, the Netherlands, and colleagues. "The
purpose of this systematic review and meta-analysis was to determine
the diagnostic performance of CTA compared with intra-arterial DSA
[digital subtraction angiography] for grading disease severity in
patients with PAD."

The reviewers searched MEDLINE from January 1966 through August 2008,
EMBASE from January 1980 through August 2008, and the Database of
Abstracts of Reviews of Effectiveness to identify studies that
compared the accuracy of CTA vs intra-arterial DSA to differentiate
the extent of PAD.

Inclusion criteria were comparison of multidetector CTA vs intra-
arterial DSA; study sample of at least 10 patients with intermittent
claudication or critical limb ischemia; testing looking for more than
50% stenosis or arterial occlusion; and presentation of either 2 x 2
or 3 x 3 contingency tables (¡Ü 50% stenosis vs > 50% stenosis or
occlusion), or provision of data allowing construction of these
tables.

Two reviewers screened studies to determine if they met inclusion
criteria and independently extracted study data. They also evaluated
methodologic quality using the quality assessment tool for diagnostic
accuracy studies (QUADAS) instrument.

Twenty (2.2%) of 909 studies identified met inclusion criteria;
median sample size in these was 33 (range, 16 - 279), and
methodologic quality was moderate. Of the total number of 957
patients enrolled, 68% had intermittent claudication.

For detection of more than 50% stenosis or occlusion, the overall
sensitivity of CTA was 95% (95% confidence interval [CI], 92% - 97%),
and specificity was 96% (95% CI, 93% - 97%). CTA accurately
identified occlusions in 94% of segments, the presence of more than
50% stenosis in 87% of segments, and the absence of significant
stenosis in 96% of segments. However, CTA overstaged 8% of segments
and understaged 15%.

"...CTA is an accurate modality to assess presence and extent of PAD
in patients with intermittent claudication; however, methodological
weaknesses of examined studies prevent definitive conclusions from
these data," the study authors write. "Nonetheless, CTA was a
reliable imaging modality with high sensitivity and specificity for
differentiating extent of disease in patients with predominantly
intermittent claudication compared with intra-arterial DSA."

Limitations of this study include exclusion of 12 studies because
they did not provide data allowing construction of 2 x 2 tables; the
possibility that important publications were missed; likely
publication bias; nonconsecutive recruitment and inclusion of only a
subset of stages of disease, resulting in possible spectrum bias;
only 4 studies clearly describing the selection criteria; incomplete
description of the patient population in many studies; most studies
including predominantly patients with intermittent claudication, who
are generally treated conservatively and do not typically require a
CTA; only 1 study including a large proportion of patients with
critical limb ischemia; and problems with the data analysis method in
the individual studies.

"Our meta-analysis also reveals that the diagnostic performance of
CTA for patients with critical limb ischemia has been poorly
investigated thus far," the review authors conclude. "More rigorous
evaluations of CTA in patients with critical limb ischemia are
needed."

The review authors have disclosed no relevant financial relationships.

JAMA. 2009;301:415-424.

Adding to a mixed evidence base regarding the use of natriuretic-
peptide levels as a treatment target in heart failure, a randomized
trial has suggested that the appealing but unproven strategy has
little or no effect on survival overall but also hinted at a possible
benefit in patients younger than 75 [1].

In the Trial of Intensified versus Standard Medical Therapy in
Elderly Patients With Congestive Heart Failure (TIME-CHF), drug
therapy guided by N-terminal brain-type natriuretic-peptide (NT-
proBNP) levels, as compared with conventional symptom-guided
management, made no significant difference to the primary end point
of hospitalization-free survival at 18 months.

The TIME-CHF results now published in the January 28, 2009 Journal of
the American Medical Association are virtually the same as those
presented in August at the European Society of Cardiology Congress
2008, reported then by heartwire.

A handful of prior studies exploring the biomarker-guided approach
produced mixed results, some showing it can improve clinical outcomes
and others showing no such advantages. A few suggested that biomarker-
guided management may tilt toward a clinical benefit in younger
patients, especially in preventing some HF hospitalizations.

That experience is somewhat consistent with TIME-CHF, which
secondarily showed across-the-board improvements in several clinical
end points with NT-proBNP guidance among its younger patients, those
no older than 75 years. Biomarker-guided management also appeared to
improve survival free of heart-failure hospitalization over the
entire study population.

In addition, write the authors, led by Dr Matthias Pfisterer
(University Hospital Basel, Switzerland), "both treatment strategies
improved symptoms and quality of life and reduced [NT-proBNP] levels
similarly over time, although these effects tended to be lower in
patients aged 75 years or older." There were also hints that
biomarker-guided therapy may have caused more "serious adverse
events" in the older group.

The current trial "is quite unique in that we looked at real-world
patients," its principal investigator, Dr Hans-Peter Brunner-La Rocca
(University Hospital Basel), told heartwire. It's the first study of
the natriuretic-peptide-guided strategy in a broad spectrum of heart-
failure patients, including the very elderly and those with multiple
comorbidities, he said. The other trials included patients who
were "at least 10 years younger, on average, than those in TIME-CHF."

The trial and clinical experience suggest that patients younger than
75 can benefit from intensified drug management, whether driven by
natriuretic peptide targets or not, according to Brunner-La
Rocca. "But in the very elderly, especially those with many
comorbidities, it's important to use the medications recommended in
the guidelines without pushing them to the highest level."

TIME-CHF entered 499 patients >60 years of age with heart failure of
at least NYHA class 2, an LVEF <45%, an HF hospitalization within the
previous year, and an NT-proBNP level >400 pg/mL for those <75 years
old or >800 pg/mL for those >75 years despite medical therapy. They
were randomized either to drug therapy aimed at pushing natriuretic-
peptide levels below those thresholds and achieving a NYHA class of 2
or better or to symptom-guided management according to US and
European guidelines and with the same functional-class goal.

Across all patients, the two groups fared similarly with respect to
the primary end point. But those younger than 75 showed a consistent
benefit from the natriuretic-peptide-guided approach. Their hazard
ratios were improved by 30% (p=0.05) for hospitalization-free
survival, 59% (p=0.02) for overall survival, and 58% (p=0.002) for HF-
hospitalization-free survival for biomarker-guided vs symptom-guided
therapy. Patients 75 or older showed no such difference for any of
the end points.

An accompanying editorial agrees that the biomarker-guided
approach "may have limited value" in the oldest patients, whereas--as
TIME-CHF suggests--it may reduce the risk of heart-failure
hospitalization in younger patients who are already well managed
pharmacologically by conventional standards [2].

"Medical therapy, therefore, can usually be further optimized and
uptitrated even in the absence of worsening symptoms--an important
clinical point," write Dr Ileana L Piña (Case Western Reserve
University, Cleveland, OH) and Dr Christopher O'Connor (Duke
University, Durham, NC).

TIME-CHF, according to the editorialists, "points to the fact that
symptom-guided medical therapy can be improved in most patients."
Indeed, "persistence in intensifying medical therapy seems to be the
key for an optimal clinical outcome in patients aged 60 to 74 years."

The reports states that TIME-CHF was 55% sponsored by the nonprofit
Horten Research Foundation; the remainder was supported by
AstraZeneca, Novartis, Menarini, Pfizer, Servier, Roche Diagnostics,
Roche Pharma, and Merck.


Pfisterer M, Buser P, Rickli H, et al. BNP-guided vs symptom-guided
heart failure therapy: The Trial of Intensified vs Standard Medical
Therapy in Elderly Patients With Congestive Heart Failure (TIME-CHF)
randomized trial. JAMA 2009; 301:383-392.
Piña IL, O'Connor C. BNP-guided therapy for heart failure. JAMA 2009;
301:432-434.

Background: Cigarette smoking is an important risk factor for
cardiovascular disease, but it is unknown whether it also contributes
to the risk of atrial fibrillation.
Methods and results: The study is part of the Rotterdam Study, a
population-based cohort study among subjects aged ¡Ý55 years. The
association between cigarette smoking and the risk of atrial
fibrillation was examined in 5,668 subjects without atrial
fibrillation at baseline. During a median follow-up of 7.2 years, 371
cases of atrial fibrillation were identified. Relative risks (RR)
were calculated with 95% CIs using the Cox proportional hazards
model, adjusted for age, gender, body mass index, hypertension,
systolic blood pressure, serum cholesterol level, diabetes mellitus,
left ventricular hypertrophy on the electrocardiogram, prevalent and
incident myocardial infarction, prevalent heart failure, and the use
of pulmonary medication.
After multivariate adjustment, current smokers and former smokers had
increased risks of atrial fibrillation as compared to never smokers
(RR 1.51, 95% CI 1.07-2.12; and RR 1.49, 95% CI 1.14-1.97,
respectively). No differences were found between men and women.
Conclusions: The results of this prospective, population-based study
show that current and former smoking of cigarettes are associated
with increased risk of atrial fibrillation.

Am Heart J.  2008;156(6):1163-1169

New guidelines on the management of aneurysmal subarachnoid
hemorrhage (aSAH) have been released by the American Heart
Association/American Stroke Association.

Among recommendations based on newly available evidence are that
these patients be treated at high-volume centers where endovascular
interventions as well as neurosurgical services are available.
Guideline authors also caution that despite having generally among
the most dramatic presentations in medicine, these hemorrhages can
present as a milder sentinel headache, and aSAH should be considered
in the differential diagnosis of all patients with new headache.

Joshua B. Bederson MD, professor and chair of the department of
neurosurgery at Mount Sinai Medical Center, in New York, and chair of
the writing group for the new guidelines, told Medscape Neurology &
Neurosurgery that aSAH is a complex process, from the initial bleed
to the devastating delayed effects of rupture.

"What has changed over the past 15 or 16 years is a gradual
improvement in understanding of many of the separate processes that
constitute the disease, as well as the evolution of some new
technologies such as endovascular treatment of aneurysms that were
really just beginning at the time of the first guidelines," Dr.
Bederson said in an interview.

The guidelines are published online January 22 in Stroke.

Improving Outcomes by Many Paths

Mortality associated with aSAH is high, about 45% in the first 30
days after a rupture, Dr. Bederson said. Still, he notes, "The
majority of aneurysms do not rupture, and as much as 1% of the
population dies of old age with a small, unruptured aneurysm."

When they do rupture, the focus of treatment has to be on both
prevention of rebleeding and management of the pathological adverse
effects that the bleed has in the brain. However, he said, "We still
have very few treatments for the hit that the brain takes during the
first seconds after the hemorrhage. Most of our progress has been in
secondary things like preventing the aneurysm from rebleeding, which
can occur in 20% of patients in the first 2 weeks."

The last guidelines document was released in 1994, and 1 of the main
changes since then has been the development of endovascular
approaches to obliteration of aneurysms. Development since that time
of the subspecialty of neurocritical care, with its own fellowships
and certification, may also have improved outcomes, Dr. Bederson
noted.

"The current standard of practice calls for microsurgical clipping or
endovascular coiling of the aneurysm neck whenever possible," the
writing group concludes. "Treatment morbidity is determined by
numerous factors, including patient, aneurysm, and institutional
factors. Favorable outcomes are more likely in institutions that
treat high volumes of patients with SAH, in institutions that offer
endovascular services, and in selected patients whose aneurysms are
coiled rather than clipped."

Other major conclusions in the new guidelines include:

SAH is frequently misdiagnosed, in up to 12% of cases. For the
initial evaluation of headache, CT scanning for suspected SAH
is "strongly recommended," followed by lumbar puncture if the CT is
negative. A standard management protocol for the evaluation of
patients with headaches and other symptoms that may potentially
relate to SAH does not currently exist and should be developed.
Early vs later treatment of the aneurysm reduces the risk for
rebleeding after SAH, and so early surgery is "reasonable and
probably indicated in the majority of cases," the authors write.
Medical measures to prevent rebleeding include blood-pressure
monitoring and control and bed rest, although these should be part of
a broader strategy with more definitive measures. A short course of
antifibrinolytics may be considered prior to definitive treatment.
To reduce poor outcomes associated with vasospasm, the
authors "strongly recommend" use of oral nimodipine. The value of
other calcium antagonists remains uncertain, they note. Treatment
begins with early management of the ruptured aneurysm, they add; "in
most cases maintaining normal circulating blood volume and avoiding
hypovolemia is probably indicated."
Another "reasonable" approach to symptomatic vasospasm is volume
expansion with induction of hypertension and hemodilution, so-
called "triple-H therapy," the authors note. "Alternatively, cerebral
angioplasty and/or selective intra-arterial vasodilator therapy may
also be reasonable, either following, or together with, or in the
place of, triple-H therapy, depending on the clinical scenario."
The relationship between hypertension and aSAH is "uncertain," they
conclude, but management of blood pressure to prevent other clinical
problems is recommended. Quitting smoking is "reasonable," they
note, "although the evidence for this association is indirect."
Screening for unruptured aneurysms in high-risk populations is
of "uncertain value," they conclude. Noninvasive imaging may be used
for such screening, "but catheter angiography remains the 'gold
standard' when it is clinically imperative to know if an aneurysm
exists."
Other recommendations in the document focus on the management of
hydrocephalus, hyponatremia, and volume contractions, as well as
seizures.

The management of aSAH is so complex that "people have really been
clamoring for recommendations or guidelines," Dr. Bederson said. The
final document is large, with over 85 pages and more than 400
references, but basically summarizes the current literature into
recommendations on each of the complex processes that run their
separate course after aSAH.

"Even if there isn't 1 major new earthshaking change, putting it all
together for the practitioner may be the most valuable part of this,"
he said.

Dr. Bederson reports he has no conflicts of interest. Disclosures for
other members of the writing group appear in the paper.

Stroke. Published online January 22, 2009.

Diastolic dysfunction is independently and strongly related to
reduced exercise capacity, a new cross-sectional study has shown [1].
And unlike many other factors associated with reduced exercise
capacity, diastolic dysfunction is modifiable and so may be a
preventable factor in the development of exercise intolerance, the
researchers point out.

Dr Jasmine Grewal (Mayo Clinic, Rochester, MN) and colleagues report
their findings in the January 21, 2009 issue of the Journal of the
American Medical Association. "This is the first time this has been
studied in a large number of patients, and it's the first time
[diastolic dysfunction] has been attempted to be related to exercise
capacity and age-related changes," senior author Dr Patricia A
Pellikka (Mayo Clinic, Rochester, MN) told heartwire.

Although she says the results need to be confirmed in prospective
trials, she says that they found "that even mild abnormalities of
diastolic function seemed to be related to a lower exercise capacity
and that the magnitude of the effect of diastolic abnormalities
became greater in older patients." This points to a potentially
modifiable factor that might be a target for interventions that could
maintain exercise capacity with aging, she says.

Diastolic Dysfunction Strongest Echocardiographic Correlate of
Exercise Tolerance

Grewal et al explain that many factors, such as advancing age, female
sex, greater body-mass index (BMI), and coexisting medical conditions
are known to be associated with a decrease in exercise capacity, but
elucidating the mechanisms of cardiac-related exercise limitation has
been technically difficult to date. Prior research has suggested that
measurements of left ventricular systolic function do not predict
maximal exercise time in people with normal or impaired left
ventricular systolic function.

Doppler echocardiography can now characterize left ventricular
diastolic function through a combination of measurements, they note,
and a few previous small studies have shown this to be correlated
with exercise capacity.

In their study, they assessed 2867 patients undergoing exercise
echocardiography with routine measurements of left ventricular
systolic and diastolic dysfunction by two-dimensional and Doppler
techniques. Analyses were conducted to determine the strongest
correlates of exercise capacity and the age and sex interactions of
these variables with exercise capacity. The main outcome measure was
exercise capacity in metabolic equivalents (METs).

Diastolic dysfunction was strongly and inversely correlated with
exercise capacity. Compared with normal function, after multivariate
adjustment, those with moderate/severe resting diastolic dysfunction
(-1.30 METs; p<0.001) and mild resting diastolic dysfunction (-0.70
METs; p<0.001) had substantially lower exercise capacity. Left
ventricular filling pressures were similarly associated with a
reduction in exercise capacity, each in separate multivariate
analyses.

Individuals with impaired relaxation (mild dysfunction) or left
ventricular filling pressure of E/e' 15 or greater had a progressive
increase in the magnitude of reduction in exercise capacity with
advancing age (p<0.001 and p=0.02, respectively). Other independent
correlates of exercise capacity were age, female sex, and BMI >30.

In this large consecutive population free of valvular heart disease
or exercise-induced ischemia referred for exercise echo, "we found
resting diastolic function to be the strongest echocardiographic
correlate of exercise tolerance," the researchers say. "This was
superseded only by the clinical factors of advancing age, female sex,
and increased BMI."

Forum moderator of theheart.org, Dr Melissa Walton-Shirley (TJ Samson
Hospital, Glasgow, KY), said: "Historically, our main focus as
cardiologists has been upon systolic dysfunction, and rightly
so . . . but this study highlights the importance of a new emphasis
on diastology and its implied role in both quality- and quantity-of-
life issues.

"When physicians have a better understanding of the physiology of
exercise intolerance, we can then translate that understanding to our
patients in the office setting or at the bedside. One of our greatest
responsibilities as healthcare providers is to convey the secrets of
wellness, longevity, and prevention to our patient population. Adult
cardiologists and pediatricians alike should take the time on a daily
basis to have these conversations that explain the negative effects
of obesity and inactivity to our patients and, more important, the
potential for reversibility of these entities," she adds.

ARBs May Have a Therapeutic Role To Play

"In identifying diastolic function parameters as strong correlates of
exercise capacity, we have identified potentially modifiable and
preventable factors in the development of exercise intolerance," the
researchers say. "It is well-known that exercise training improves
diastolic function in healthy individuals, [but] the effects of
training on diastolic dysfunction are less clear," they add.

Pellikka expanded upon this for heartwire: "Work needs to be done to
see if we can modify this age-related decline in exercise capacity.
We know certain risk factors--such as uncontrolled hypertension and
untreated coronary disease--will lead to diastolic dysfunction, so we
need to make sure we're treating those conditions aggressively.

"Patients with unexplained limitations of exercise capacity or
patients with exertional symptoms should have their diastolic
function assessed, and fortunately that is something that is widely
available and can be achieved with echo Doppler completely
noninvasively," she notes.

One possible therapy is angiotensin-receptor blockers (ARBs), she
says, which appear promising because they block the angiotensin II
action that is thought to be responsible for slowed left ventricular
relaxation during exercise.

"Although these data require confirmation in prospective studies,
they point to a potentially modifiable factor that might be a target
for interventions that could maintain exercise capacity with aging."


Grewal J, McCully RB, Kane GC, et al. Left ventricular function and
exercise capacity. JAMA 2009; 301:286-294.

In the alternative, it tells us the entire preoccupation with cholesterol is
nonsense.

   ----- Original Message -----
   From: dr_allen_wang
   To: heart119@yahoogroups.com
   Sent: Thursday, January 22, 2009 11:21 PM
   Subject: [Heart119] Majority of Patients Hospitalized With CAD at
Guideline-Recommended LDL Targets


   A majority of patients hospitalized with coronary artery disease
   (CAD) have LDL-cholesterol levels considered normal by current
   guidelines, a new study has shown [1]. The findings suggest that
   current lipid targets are not low enough to prevent risk in patients
   who would benefit, say researchers.

   "There have been modest improvements in LDL-cholesterol levels over
   time," lead investigator Dr Gregg Fonarow (University of California
   Los Angeles Medical Center) told heartwire. "One of the major
   findings of this study that should serve as a wake-up call for anyone
   interested in reducing death and disability due to cardiovascular
   disease is that nearly 75% of patients having first ACS events had
   LDL levels below 130 mg/dL, and nearly 50% had LDL levels below 100
   mg/dL."

   The study is published in the January 2009 issue of the American
   Heart Journal with lead investigator Dr Amit Sachdeva (University of
   California, Los Angeles Medical Center).

   GWTG Database

   The new data, obtained from a national database sponsored by the
   American Heart Association Get With the Guidelines program, includes
   admission lipid levels on 137 000 individuals from more than 500
   hospitals who were admitted with CAD. Admission diagnoses were most
   commonly related to acute coronary syndromes.

   Before admission to the hospital, 21% of patients were taking lipid-
   lowering medications. Among patients with a medical history of CAD,
   other atherosclerotic vascular disease, or diabetes, just 29.4% were
   taking lipid-lowering therapy prior to hospital admission, compared
   with 14% of patients without a history of CAD.

   The mean LDL-cholesterol level among hospitalized patients was 104.9
   mg/dL. Of these, almost 50% of patients had LDL-cholesterol levels
   <100 mg/dL, with 17% of patients having LDL levels lower than the
   more stringent target of <70 mg/dL. In the total cohort, roughly 75%
   of patients had levels <130 mg/dL.

   Regarding HDL-cholesterol levels, 54.6% of patients hospitalized had
   levels <40 mg/dL and only 7.8% of patients had levels that exceeded
   60 mg/dL. Just 1.4% of patients hospitalized with CAD had ideal
   levels of LDL and HDL cholesterol.

   "The conventional cholesterol guidelines are missing the majority of
   patients having cardiovascular events," said Fonarow. "While
   certainly there are other risk factors beyond LDL, there are hundreds
   of thousands of potentially preventable cardiovascular events
   occurring because the LDL levels for primary prevention are missing
   too many individuals."

   Among patients without established vascular disease or diabetes, 42%
   of patients had LDL-cholesterol levels <100 mg/dL and 72% had levels
   <130 mg/dL. On the other hand, 52% of patients without established
   disease had HDL cholesterol levels <40 mg/dL.

   Low HDL was observed in a majority of patients presenting with first
   and recurrent cardiovascular events, noted Fonarow. "Finding safe,
   well-tolerated, and effective therapies to raise cardioprotective HDL
   appears to be very important," he added. "However, it is essential
   that large-scale trials be conducted to demonstrate reduction in
   clinical events incremental to LDL lowering with statin therapy and
   that the benefits of treating HDL outweigh potential risks."

   The group also points out that a large proportion of patients
   included in the present study could reach the standard or optional
   National Cholesterol Education Program (NCEP) LDL goals without
   statin therapy or with a statin dose lower than used in clinical
   trials.

   Sachdeva A, Cannon CP, Deedwania PC, et al. Lipid levels in patients
   hospitalized with coronary artery disease: an analysis of 136,905
   hospitalizations in Get With the Guidelines. Am Heart J 2009; 157:111-
   117. Abstract





[Non-text portions of this message have been removed]

A majority of patients hospitalized with coronary artery disease
(CAD) have LDL-cholesterol levels considered normal by current
guidelines, a new study has shown [1]. The findings suggest that
current lipid targets are not low enough to prevent risk in patients
who would benefit, say researchers.

"There have been modest improvements in LDL-cholesterol levels over
time," lead investigator Dr Gregg Fonarow (University of California
Los Angeles Medical Center) told heartwire. "One of the major
findings of this study that should serve as a wake-up call for anyone
interested in reducing death and disability due to cardiovascular
disease is that nearly 75% of patients having first ACS events had
LDL levels below 130 mg/dL, and nearly 50% had LDL levels below 100
mg/dL."

The study is published in the January 2009 issue of the American
Heart Journal with lead investigator Dr Amit Sachdeva (University of
California, Los Angeles Medical Center).

GWTG Database

The new data, obtained from a national database sponsored by the
American Heart Association Get With the Guidelines program, includes
admission lipid levels on 137 000 individuals from more than 500
hospitals who were admitted with CAD. Admission diagnoses were most
commonly related to acute coronary syndromes.

Before admission to the hospital, 21% of patients were taking lipid-
lowering medications. Among patients with a medical history of CAD,
other atherosclerotic vascular disease, or diabetes, just 29.4% were
taking lipid-lowering therapy prior to hospital admission, compared
with 14% of patients without a history of CAD.

The mean LDL-cholesterol level among hospitalized patients was 104.9
mg/dL. Of these, almost 50% of patients had LDL-cholesterol levels
<100 mg/dL, with 17% of patients having LDL levels lower than the
more stringent target of <70 mg/dL. In the total cohort, roughly 75%
of patients had levels <130 mg/dL.

Regarding HDL-cholesterol levels, 54.6% of patients hospitalized had
levels <40 mg/dL and only 7.8% of patients had levels that exceeded
60 mg/dL. Just 1.4% of patients hospitalized with CAD had ideal
levels of LDL and HDL cholesterol.

"The conventional cholesterol guidelines are missing the majority of
patients having cardiovascular events," said Fonarow. "While
certainly there are other risk factors beyond LDL, there are hundreds
of thousands of potentially preventable cardiovascular events
occurring because the LDL levels for primary prevention are missing
too many individuals."

Among patients without established vascular disease or diabetes, 42%
of patients had LDL-cholesterol levels <100 mg/dL and 72% had levels
<130 mg/dL. On the other hand, 52% of patients without established
disease had HDL cholesterol levels <40 mg/dL.

Low HDL was observed in a majority of patients presenting with first
and recurrent cardiovascular events, noted Fonarow. "Finding safe,
well-tolerated, and effective therapies to raise cardioprotective HDL
appears to be very important," he added. "However, it is essential
that large-scale trials be conducted to demonstrate reduction in
clinical events incremental to LDL lowering with statin therapy and
that the benefits of treating HDL outweigh potential risks."

The group also points out that a large proportion of patients
included in the present study could reach the standard or optional
National Cholesterol Education Program (NCEP) LDL goals without
statin therapy or with a statin dose lower than used in clinical
trials.


Sachdeva A, Cannon CP, Deedwania PC, et al. Lipid levels in patients
hospitalized with coronary artery disease: an analysis of 136,905
hospitalizations in Get With the Guidelines. Am Heart J 2009; 157:111-
117. Abstract

A majority of patients hospitalized with coronary artery disease
(CAD) have LDL-cholesterol levels considered normal by current
guidelines, a new study has shown [1]. The findings suggest that
current lipid targets are not low enough to prevent risk in patients
who would benefit, say researchers.

"There have been modest improvements in LDL-cholesterol levels over
time," lead investigator Dr Gregg Fonarow (University of California
Los Angeles Medical Center) told heartwire. "One of the major
findings of this study that should serve as a wake-up call for anyone
interested in reducing death and disability due to cardiovascular
disease is that nearly 75% of patients having first ACS events had
LDL levels below 130 mg/dL, and nearly 50% had LDL levels below 100
mg/dL."

The study is published in the January 2009 issue of the American
Heart Journal with lead investigator Dr Amit Sachdeva (University of
California, Los Angeles Medical Center).

GWTG Database

The new data, obtained from a national database sponsored by the
American Heart Association Get With the Guidelines program, includes
admission lipid levels on 137 000 individuals from more than 500
hospitals who were admitted with CAD. Admission diagnoses were most
commonly related to acute coronary syndromes.

Before admission to the hospital, 21% of patients were taking lipid-
lowering medications. Among patients with a medical history of CAD,
other atherosclerotic vascular disease, or diabetes, just 29.4% were
taking lipid-lowering therapy prior to hospital admission, compared
with 14% of patients without a history of CAD.

The mean LDL-cholesterol level among hospitalized patients was 104.9
mg/dL. Of these, almost 50% of patients had LDL-cholesterol levels
<100 mg/dL, with 17% of patients having LDL levels lower than the
more stringent target of <70 mg/dL. In the total cohort, roughly 75%
of patients had levels <130 mg/dL.

Regarding HDL-cholesterol levels, 54.6% of patients hospitalized had
levels <40 mg/dL and only 7.8% of patients had levels that exceeded
60 mg/dL. Just 1.4% of patients hospitalized with CAD had ideal
levels of LDL and HDL cholesterol.

"The conventional cholesterol guidelines are missing the majority of
patients having cardiovascular events," said Fonarow. "While
certainly there are other risk factors beyond LDL, there are hundreds
of thousands of potentially preventable cardiovascular events
occurring because the LDL levels for primary prevention are missing
too many individuals."

Among patients without established vascular disease or diabetes, 42%
of patients had LDL-cholesterol levels <100 mg/dL and 72% had levels
<130 mg/dL. On the other hand, 52% of patients without established
disease had HDL cholesterol levels <40 mg/dL.

Low HDL was observed in a majority of patients presenting with first
and recurrent cardiovascular events, noted Fonarow. "Finding safe,
well-tolerated, and effective therapies to raise cardioprotective HDL
appears to be very important," he added. "However, it is essential
that large-scale trials be conducted to demonstrate reduction in
clinical events incremental to LDL lowering with statin therapy and
that the benefits of treating HDL outweigh potential risks."

The group also points out that a large proportion of patients
included in the present study could reach the standard or optional
National Cholesterol Education Program (NCEP) LDL goals without
statin therapy or with a statin dose lower than used in clinical
trials.


Sachdeva A, Cannon CP, Deedwania PC, et al. Lipid levels in patients
hospitalized with coronary artery disease: an analysis of 136,905
hospitalizations in Get With the Guidelines. Am Heart J 2009; 157:111-
117. Abstract

New data from a single center suggest that transradial-access PCI can
be performed successfully in complex patients and complex lesions,
such as in acute-MI patients and those older than 80 years of age
[1].

Presenting the data at the International Symposium of Endovascular
Therapy, researchers also showed that radial-access interventions can
be successfully performed in patients with complex lesions, including
chronic total occlusions and bifurcated branches.

"We feel very strongly that the radial approach is the way to go,"
lead investigator Dr Ramon Quesada (Baptist Cardiac and Vascular
Institute, Miami, FL) told heartwire. "It is good for the patient,
results in fewer complications, decreases hospital length of stay,
and the patients love it. Importantly, with these subgroups, we're
showing that everything we do with the femoral approach can also be
done radially."

Presenting data this week on their experience with transradial
interventions at Baptist Cardiac and Vascular Institute, Quesada
noted that the group has performed nearly 700 complex transradial
interventions since 2003. The procedural success rates range from as
high as 98.5% in patients with complex B2-C lesions to 78.9% in
patients with chronic total occlusions. Among acute-MI patients, the
procedural success rate is 97%.

Bleeding risks also remained low, said Quesada, with resolved radial-
access site hematomas occurring in 2.2% of patients with complex
lesions and 5.6% of patients with bifurcated branches. Of the 134
acute-MI patients treated with radial access since 2003, there were
three small hematomas that were resolved.

The group also notes that octogenarians also fare well with the
transradial approach, although tortuosity of the vessels is the
biggest complication in this patient population. Among these
patients, vascular complications declined from 15% via the femoral
approach to less than 2% with radial-access PCI, Quesada told
heartwire.

Proponents of the transradial approach, like Quesada, who has been
performing radial-access PCI for 10 years and who now does 80% of his
cases via the radial artery, point to recent studies and meta-
analyses showing that the technique is associated with equivalent
procedural success to femoral access. Along with the equivalent
success, however, are lower rates of bleeding and vascular
complications, even among high-risk patients.

Still, despite the arguments in favor of the approach, radial-access
PCI is rarely performed. One of the largest and most recent studies
identified nearly 600 000 patients who underwent PCI between January
2004 and March 2007, with only 1.32% treated using radial-artery
access. Despite the limited use of radial PCI, the approach was
associated with a similar rate of success and a 58% lower risk of
bleeding complications.

"The biggest drawback to the procedure is the learning curve," said
Quesada. "It's a more difficult technique to master, but when you get
it down you are able to have the same success as when you use the
femoral approach. We're not saying that every interventionalist
should rush out and start doing these, or start doing them on MI
patients. That would be stupid. Start with a diagnostic and work your
way from there."


Quesada R. Complex transradial interventions for CTOs and STEMI.
International Symposium on Endovascular Therapy; January 19, 2009;
Hollywood, FL.

The severity of incident MIs has dropped significantly in the US over
a 15-year period, a new analysis of the Atherosclerosis Risk in
Communities Study (ARIC) has shown [1]. This has likely contributed
to a decline in populationwide death rates for coronary heart disease
(CHD), say Dr Merle Myerson (St Luke's Roosevelt Hospital, New York,
NY) and colleagues in their report published online January 19, 2009
in Circulation.

"Our severity indicators all seemed to indicate that MIs were less
severe, the cardiac enzymes did not go as high, and there were fewer
Q waves on ECG. This is very good, because if people have less severe
heart attacks, the chances are less that they'll die," Myerson told
heartwire.

"Although this study was not particularly designed to tell us exactly
why heart attacks are less severe, it certainly appears that better
in-hospital care and better prevention beforehand may have played a
role," she added. One thing that has not improved, however, is the
time it takes people to get to the hospital. "We were surprised to
find this, because efforts have been made through public-education
programs. But we didn't see any improvement, and this is in agreement
with several other studies," she noted.

Consistent Picture Showing Clear Decline in MI Severity

The new study by Myerson et al extends previous findings from ARIC,
an ongoing epidemiologic trial that includes data from four areas--
Forsythe County, NC, including Winston-Salem; Washington County, MD,
including Hagerstown; and the suburbs of Minneapolis, MN and Jackson,
MS.

In the previous analysis, focusing on 1987 to 1994, researchers found
a decrease in many but not all indicators of severity. This new study
includes an extra eight years of data, covering 10 285 patients, ages
35 to 74, who were discharged from the hospital diagnosed with a
definite or probable first-time heart attack from January 1, 1987
through December 31, 2002.

"We wanted to explore why mortality from CHD has declined, to see
whether we can discover what's working and what's not working,"
Myerson explained to heartwire. The new findings show a more
consistent picture, with a clear decline in severity of heart
attacks, she says.

MI classification was assigned according to an algorithm consisting
of chest pain, ECG evidence, and cardiac biomarkers. The number of MI
cases with major ECG abnormalities declined as shown by a 1.9%/year
decline (p=0.002) in the proportion of those with initial ST-segment
elevation, a 3.9%/year drop (p<0.001) in those with subsequent Q
waves, and a 4.5%/year reduction (p<0.001) in those with any major Q
wave. Maximum creatinine kinase and creatinine kinase-MB values also
fell (by 5.2% and 7.6%; p<0.001 and p<0.001 per year, respectively),
although in later years maximum troponin I values remained stable.

But the percentage of patients who arrived at the hospital less than
two hours after symptom onset remained unchanged over the course of
the study, at approximately 33%.

Study Findings Generalizable

Myerson says one of the key strengths of ARIC is its
generalizability.

"We had four geographic areas--including urban, rural, and suburban--
and we have men and women and blacks and whites in this study," she
says. "And while we certainly can't say we captured everybody in this
country, the beauty and strength of the ARIC study is that we can
say, 'Hey, we're finding it in each of these populations.' "

The results likely indicate that risk factors, such as blood pressure
and cholesterol, are being better controlled, says Myerson, and that
when people do get to the hospital there has been an improvement in
care there. "Attributing the reduction in severity to specific causes
will be an important next step, so that effective strategies can be
reinforced and public-health policies can be better directed," she
concludes.


Myerson M, Coady S, Taylor H, et al. Declining severity of myocardial
infarction from 1987 to 2002. The Atherosclerosis Risk in Communities
(ARIC) Study. Circulation 2009; 119:503-514. Abstract

A series of papers in a special issue of Circulation is highlighting
new data on cardiovascular disease in Asians specifically. The
researchers stress that the presentation of disease there is often
different from that seen in the West, and responses to treatment can
also differ, necessitating separate study in Asian populations. And
given that it is now widely acknowledged that 85% of cardiovascular
deaths worldwide will soon occur in low- and middle-income countries,
there is a pressing need for such research, they note.

Dr Hirotsugu Ueshima (Shiga University of Medical Science, Otsu,
Japan) and colleagues review the whole subject of cardiovascular
disease and risk factors in Asia in the December 16, 2008 issue of
Circulation [1]. They note that many countries in Asia have greater
mortality and morbidity from stroke than from coronary heart disease
(CHD), "whereas the opposite is true in Western countries," and they
emphasize the high prevalence of hypertension in some Asian nations.
They also point out that, in most Asian countries, mean levels of
total cholesterol are lower than those found in Western countries.

In fact, a new report from the INTERHEART study, published separately
in the January 20, 2009 issue of the Journal of the American College
of Cardiology, has found that the low-density lipoprotein cholesterol
(LDL-C) threshold for treatment may be lower in Asians, perhaps
necessitating a rethinking of treatment targets there [2].

In an editorial accompanying the Circulation papers [3], Dr Shigetake
Sasayama (Doshisha University, Kyoto, Japan) says: "It is our hope
that this issue provides a clear exposition of the current state of
cardiovascular disease in Asia and provides readers with a better
understanding of some of these diseases, with an emphasis on therapy
and insight into specific problems that face patients suffering from
cardiovascular disease in Asia."

Stroke on the Rise in India, on the Wane in Japan

Two of the new papers in Circulation detail the current picture on
stroke in India and Japan, respectively, and another discusses the
situation with regard to hypertension in China.

In their paper [4], Indian physicians Drs Shyamal Kumar Das and Tapas
Kumar Banerjee (Bangur Institute of Neurosciences and Psychiatry,
Kolkata, India) say, "The data accumulated so far are sufficient for
us to declare that stroke in India is very much on the rise," and
they note that in the past decade in particular, some critical data
on stroke in India have become available.

"Management of hypertension, the most important risk factor in the
community, is far from satisfactory," they point out, noting that a
high prevalence of cerebral hemorrhage has been documented in eastern
India. "Similar studies need to be conducted in different parts of
India to develop a national stroke registry . . . that would define
criteria, dietary, and risk factors because India is a multiethnic
and multicultural country."

Data on long-term outcome of stroke, the influence of socioeconomic
factors on its occurrence, and an estimate of the economic burden of
the condition are also essential to allow for adequate allocation of
resources by healthcare planners, they note.

And finally, there is "an urgent need for undertaking health
education . . . about the awareness of risk factors and early warning
signs of stroke in the community," they stress.

Meanwhile, in Japan, new data show that the incidence of ischemic
stroke has declined significantly over the past 40 years, say Dr
Michiaki Kubo (Center for Genomic Medicine, RIKEN, Yokohama,
Kanagawa, Japan) and colleagues [5].

They examined three cohorts of people over the age of 40 in 1961,
1974, and 1988 in the Japanese community of Hisayama. Morphological
exams by autopsy or brain imaging were performed on most of the
ischemic-stroke cases in these cohorts. When 13-year follow-up data
were compared, the age-adjusted incidence of ischemic stroke and
lacunar infarction declined significantly from the first to the third
cohort for both sexes, whereas the incidences of atherothrombotic and
cardioembolic infarction did not change during this period.

They believe that improved control of hypertension would largely have
influenced this declining trend: the age-adjusted and sex-adjusted
hazard ratio of hypertension decreased from 3.25 in the first cohort
to 1.83 in the third cohort.

But they warn that hypertension "still makes a large contribution to
the development of ischemic stroke, [and] there is a need for greater
primary-prevention efforts in the treatment of hypertension and
metabolic disorders."

Hypertension Remains a Huge Problem in China

Meanwhile, Dr Yanfeng Wu (Peking University of Public Health,
Beijing, China) and colleagues, in their report [6], attempt to
provide accurate estimates of the prevalence, awareness, and control
of hypertension in adults in China. Despite evidence to the contrary,
the figures suggest that the ratio of controlled to treated
hypertension has remained largely unchanged, at 1:4, over the past
decade, they note.

Using data obtained from the China National Nutrition and Health
Survey 2002, they discovered that around one in six Chinese is
hypertensive, equating to around 153 million adults, but only one-
quarter are aware of their condition.

The prevalence of hypertension was higher among men than women (20%
vs 17%; p<0.001) and was higher in successive age groups. The
prevalence of hypertension was also higher in urban compared with
rural areas for both sexes.

"National hypertension programs must focus on improving awareness in
the wider community, as well as treatment and control, to prevent
many tens of thousands of cardiovascular-related deaths," they
conclude.

Reduce Salt Consumption, Smoking in Asia

In wrapping up the Circulation issue, Ueshima and colleagues make
some important observations. While total cholesterol intake has
traditionally been low in Asia, the recent Westernization in many
countries there is beginning to change this, resulting in the
prevalence of obesity and diabetes increasing, they note. As in the
West, management of the traditional risk factors for CVD is just as
important for prevention in Asian nations, they stress.

And specifically, "reduction in salt consumption in East Asian
countries . . . is important for the reduction of CVD, especially
stroke. Prevention of smoking is also an important strategy for
reducing CVD in most Asian countries, especially for men," they
conclude.

New INTERHEART Analysis Shows Mean LDL-C Lower in Asians

The new analysis from the INTERHEART study may help illuminate the
picture further with regard to cholesterol and Asian populations.

Dr Ganesan Karthikeyan (McMaster University, Hamilton, ON) and
colleagues recruited 5731 cases of a first AMI and 6459 control
subjects from 65 centers in Asia. They obtained plasma levels of
lipids and apolipoproteins in the different Asian subgroups (South
Asians, Chinese, Southeast Asians, and Japanese) and correlated these
with the risk of AMI.

Among both cases and controls, mean LDL-C levels were about 10-mg/dL
lower compared with non-Asians, and HDL-C levels were slightly lower
among Asians compared with non-Asians.

But despite these differences in absolute levels, the risk of AMI
associated with increases in LDL-C and decreases in HDL-C was similar
for Asians and non-Asians. And in South Asians in particular, changes
in apolipoprotein predicted risk better than HDL-C (South Asians were
much more likely than other Asians to have low HDL-C).

"Although Asian patients are likely to benefit from lowering LDL-C,
the threshold for treatment initiation and the treatment targets are
conceivably lower than for Caucasians. These thresholds and targets
need to be determined in future studies," say Karthikeyan et al.

Also, in South Asians--given their lower levels of HDL-C--approaches
to increasing HDL-C may also be beneficial, they conclude.

The INTERHEART study was funded by unrestricted grants from several
pharmaceutical companies, which are listed in the paper.


Ueshima H, Sekikawa A, Miura K, et al. Cardiovascular disease and
risk factors in Asia. A selected review. Circulation 2008; 118: 2702-
2709. Abstract
Karthikeyan G, Teo KK, Islam S, et al. Lipid profile, plasma
apolipoproteins, and risk of a first myocardial infarction among
Asians. An analysis from the INTERHEART study. J Am Coll Cardiol
2009; 53: 244-253.
Sasayama S. Heart disease in Asia. Circulation 2008; 118: 2669-2671.
Abstract
Das SK and Banerjee TK. Stroke. Indian scenario. Circulation 2008;
118: 2719-2724. Abstract
Kubo M, Hata J, Doi Y, et al. Secular trends in the incidence of and
risk factors for ischemic stroke and its subtypes in Japanese
population. Circulation 2008; 118: 2672-2678. Abstract
Wu Y, Huxley R, Li L, et al. Prevalence, awareness, treatment and
control of hypertension in China. Data from the China National
Nutrition and Health Survey 2002. Circulation 2008; 118: 2679-2686.
Abstract

Results of 2 new MRI analyses from the Women's Health Initiative
Memory Study (WHIMS) show that hormone therapy (HT) is associated
with increased brain atrophy, but not with subclinical
cerebrovascular disease.

The findings suggest that brain atrophy, not ischemic brain lesions,
may underlie the increase in dementia and decrease in global
cognitive functioning with HT seen in the WHIMS study.


Laura H. Coker, PhD, from Wake Forest University, in Winston-Salem,
North Carolina, took the lead on the paper looking at subclinical
cerebrovascular disease, which was actually the primary analysis. The
results were surprising, the authors note.

"We saw very little difference in brain-lesion volumes between women
who had taken the estrogen-based hormone therapy and women who had
taken placebo," Dr. Coker told Medscape Neurology & Neurosurgery.

Susan M. Resnick, PhD, from the Biomedical Research Center, National
Institute on Aging, in Baltimore, Maryland, was lead author on the
brain-volumes study. "Overall, women who had been randomized to
receive hormone therapy had slightly smaller hippocampal and frontal
volumes, both structures critical in maintaining normal memory
function," Dr. Resnick told Medscape Neurology & Neurosurgery. The
greatest negative effects were found among women with the lowest
cognitive function at baseline, prior to the start of hormone
therapy.

Both papers are published in the January 13 issue of Neurology.

Brain Lesions

WHIMS was an ancillary study to the landmark Women's Health
Initiative trial that showed, contrary to previous observational
evidence, that conjugated equine estrogens (CEE), alone and in
combination with medroxyprogesterone acetate (MPA), increased the
risk for heart disease, stroke, and breast cancer in postmenopausal
women.

WHIMS looked specifically at dementia and global cognitive decline in
women 65 years of age and older and found increases in both of these
end points with CEE treatment, again with or without MPA.

The WHIMS-MRI study was undertaken to explore these results further,
looking at potential mechanisms of the adverse effects using magnetic
resonance imaging (MRI). The most likely suspect was subclinical,
or "silent," strokes, the authors reasoned, since clinical stroke was
also increased with hormone therapy in the main WHI trial.

A subset of 1403 women underwent MRI an average of 3 years after the
trial for those in the CEE-plus-MPA trial and 1.4 years for the CEE-
alone trial participants. Average follow-up during the trials
themselves were 4 and 5.6 years, respectively.

The primary outcome measure of the WHIMS-MRI study was total ischemic-
lesion volume, reported in the paper by Dr. Coker and colleagues.
Results showed mean ischemic lesion volumes were slightly larger for
the CEE-plus-MPA group vs placebo, except for the basal ganglia, but
the differences were not significant. Lesion volumes for those on CEE
alone were similar to those on placebo.

"This finding was consistent within each trial and in pooled analyses
across trials," the authors conclude.

Lesion volumes did correlate with age, smoking, a history of
cardiovascular disease, hypertension, lower posttrial global
cognition scores, and increased incident cases of mild cognitive
impairment or probable dementia either during or after the trial.

Brain Volumes

In the same subset of 1403 women, Dr. Resnick and colleagues looked
at total brain, ventricular-, hippocampal-, and frontal-lobe volumes,
after adjustment for age, clinic site, estimated intracranial volume,
and dementia risk factors.

The authors found that the covariate-adjusted mean frontal-lobe
volume was 2.37 cubic cm lower among women assigned to HT compared
with placebo (P = .004). Mean hippocampal volume was slightly lower,
they note (0.10 cubic cm, P = .05), and the difference between groups
in total brain volume approached statistical significance (P = .07).
The results were similar whether women received CEE plus MPA or CEE
alone.

The loss in hippocampal volume was greatest in women who had the
lowest Mini-Mental State Examination scores at baseline, Dr. Resnick
noted, "suggesting that the therapy may have accelerated a
neurodegenerative process that had already begun."

The hormone regimens selected were the most widely used at the time
these trials were begun, Dr. Resnick noted. Since then, other studies
have been undertaken looking at the effects of estradiol, the natural
form of the hormone, as well as the effects of treatment in women who
begin hormone therapy closer to menopause.

In WHIMS, all the women were 65 years of age and older when they
began HT, which may have been too late. However, Dr. Resnick
noted, "it didn't really make sense to look at dementia in 50-year-
olds."

Women who were 50 years at baseline were included in the overall WHI
study, Dr. Resnick said. "One of the things that Dr. [Sally] Shumaker
and Dr. Coker and their colleagues are going to do is go back and
look at those women who were treated when they were 50 to 65 ¡X it's
10 years later ¡X and look at their cognitive function now.

"It's really a hypothesis, but there may be a window of opportunity
such that if women are treated early you may have a different outcome
than you would if you're treated later," she said.

In the meantime, Dr. Coker said, "these findings provide more
evidence to help women make decisions about HT." Those 65 years of
age and older should not begin HT, because the risks outweigh
possible benefits, she said. However, "these findings do not inform
the guidelines for newly menopausal women. The current
recommendations are that HT be used only if needed to treat
menopausal symptoms and be taken at the lowest dose and for the
shortest time possible."


The Women's Health Initiative and the WHIMS-MRI study were funded by
the National Heart, Lung, and Blood Institute, US Department of
Health and Human Services. WHIMS was funded in part by Wyeth
Pharmaceuticals. Dr. Resnick reports no disclosures; disclosure
information for coauthors appears in the paper. Dr. Coker reports no
disclosures.

Neurology. 2009;72:125-134 Abstract,135-142. Abstract

A scientific statement from the American Heart Association (AHA)
outlines what is known and what is yet to be learned regarding a
familiar array of cardiometabolic risk factors manifested in children
and adolescents, emphasizing, in particular, that its clinical
implications are poorly understood in that population, especially
compared with what is known about it in adults [1].

Whether combinations of obesity, insulin resistance, lipid
abnormalities, and hypertension in the young actually predict
cardiovascular disease during the adult years is not known, in part
because of a dearth of longitudinal data and some unique challenges
in even defining those conditions in children, according to the
report's writing group, chaired by Dr Julia Steinberger (University
of Minnesota, Minneapolis).

"In adults, we refer to this clustering of risk factors as the
metabolic syndrome, but it hasn't been clear to us that it could be
called the metabolic syndrome in children," Steinberger, a pediatric
cardiologist, told heartwire.

She described the report as an update to a 2003 statement from the
AHA on obesity, insulin resistance, and diabetes in the young [2],
and a "pediatric companion document" to the organization's Diagnosis
and Management of the Metabolic Syndrome consensus statement from
2005 [3]. The report was published online January 12, 2009 by
Circulation and is scheduled for the February 3 issue.

It has been common in pediatric studies to characterize the metabolic
syndrome in terms of definitions used for adults, observed
Steinberger. But that approach, as well as some attempts to create
child-specific definitions, has been limited, among other reasons, by
a lack of outcomes data and variability in the measures of the
different risk factors. It isn't practical to track children long
enough for some of them to develop cardiovascular disease and
experience clinical events, and what's "abnormal" for some will
be "normal" for others.

"In adults, we can use cut points for defining normal and abnormal
levels of the components of the metabolic syndrome," Steinberger
said. "In children it¡¦s a lot more vague because we're talking about
children of different ages and in different stages of development.
Waist circumference, triglycerides, HDL-cholesterol, blood pressure,
fasting glucose--in children these are moving targets, there really
aren't very well established criteria for what is normal or
abnormal."

So the challenge in kids, as reflected in the AHA scientific
statement, is to define who is at risk for disease in adulthood in
terms of the different risk factors, with less attention paid to
establishing criteria for defining a specific syndrome, according to
Steinberger. Whereas in adults there is a focus on the treatment of
disease resulting from the metabolic syndrome, she said, in kids the
focus is on prevention and management of obesity and the other risk
factors.

"Because specific treatment aimed at the underlying pathophysiology
of the metabolic syndrome does not yet exist, other than reducing
adiposity and increasing physical activity, therapy targeted at each
of the risk factors present is of importance. This treatment strategy
would not be improved by labeling a patient dichotomously as having
the metabolic syndrome," according to the statement.

"What is probably needed is not a dichotomous definition but a more
complex weighted scoring system that takes into account the magnitude
of all of the risk factors, their interaction, and other important
patient characteristics, including family history."

Steinberger reports receiving research grants from Pfizer and Sankyo.
Disclosures for other members of the statement's writing group are in
the report.

Steinberger J, Daniels SR, Eckel RH, et al. Progress and challenges
in metabolic syndrome in children and adolescents. A scientific
statement from the American Heart Association Atherosclerosis,
Hypertension, and Obesity in the Young Committee of the Council on
Cardiovascular Disease in the Young; Council on Cardiovascular
Nursing; and Council on Nutrition, Physical Activity, and Metabolism.
Circulation; published online before print January 12, 2009. Abstract
Steinberger J, Daniels SR. Obesity, insulin resistance, diabetes and
cardiovascular risk in children: an American Heart Association
scientific statement from the Atherosclerosis, Hypertension, and
Obesity in the Young Committee (Council on Cardiovascular Disease in
the Young) and the Diabetes Committee (Council on Nutrition, Physical
Activity, and Metabolism). Circulation 2003; 107:1448 ¡V1453.
Abstract
Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and management of
the metabolic syndrome: an American Heart Association/National Heart,
Lung, and Blood Institute Scientific Statement. Circulation 2005;
112:2735¡V2752. Abstract

Early postnatal prophylactic granulocyte-macrophage colony
stimulating factor (GM-CSF) corrects neutropenia but does not lower
risk for sepsis or improve survival and short-term outcomes in
extremely preterm neonates, according to the results of a single-
blind, multicenter, randomized controlled trial reported in the
January 17 issue of The Lancet.

"Systemic sepsis is a major cause of death in preterm neonates,"
write Robert Carr, from the Department of Haematology, Guy's and St
Thomas' Hospital, King's College, London, United Kingdom, and
colleagues. "There are compelling theoretical reasons why treatment
with haemopoietic [CSFs] might reduce sepsis and improve outcomes,
and as a consequence these agents have entered into use in neonatal
medicine without adequate evidence. We assessed whether [GM-CSF]
administered as prophylaxis to preterm neonates at high risk of
neutropenia would reduce sepsis, mortality, and morbidity."

The trial of GM-CSF administered as prophylaxis for reduction of
sepsis in extremely preterm neonates who were small for gestational
age (the PROGRAMS trial) took place in 26 centers between June 2000
and June 2006. Within 72 hours of birth, 280 neonates of 31 weeks'
gestation or less and below the 10th percentile for birth weight were
randomly assigned either to treatment with GM-CSF, 10 µg/kg per day
subcutaneously for 5 days, or to standard care.

The treating clinicians completed a detailed clinical record form
daily from recruitment to day 28. The main study endpoint was sepsis-
free survival to 14 days from trial entry, and analysis was by
intention to treat.

During the first 11 days, infants treated with GM-CSF had a
significantly more rapid increase in neutrophil counts after trial
entry than did control infants (difference between neutrophil count
slopes, 0.34 ¡Ñ 109/L/day; 95% confidence interval [CI], 0.12 ¡X
0.56). However, sepsis-free survival was not significantly different
for all infants (93 of 139 treated infants, 105 of 141 control
infants; difference, −8%; 95% CI, −18 to 3). A meta-analysis
including data from this study and from previous published
prophylactic trials showed no benefit in survival.

"Early postnatal prophylactic GM-CSF corrects neutropenia but does
not reduce sepsis or improve survival and short-term outcomes in
extremely preterm neonates," the study authors write.

Study limitations include time to enrollment delayed by the need for
informed parental consent and inability to determine the effect of GM-
CSF as adjuvant treatment for established sepsis.

"We believe that, before embarking on future single agent clinical
trials, we should consider if this is too simplistic an approach to
sepsis prevention in the preterm infant, whose immune system appears
compromised in many different ways," the study authors
conclude. "Knowledge of the functional characteristics of neonatal
innate immunity remains limited and needs continued research effort.
Successful future stratagems will need a wider view of their
antibacterial defences."

In an accompanying comment, Frank Shann, MD, from the Intensive Care
Unit, Royal Children's Hospital, in Melbourne, Australia, notes that
about 90% of babies receive at least 1 off-label or unlicensed drug
during a stay in intensive care, and that some of these untested
treatments are ineffective or even harmful.

"Although leucopheresis is far more difficult than giving injections
of G-CSF or GM-CSF, the procedure is much easier to do than in the
early 1980s; perhaps the time is right for a large randomised trial
in neonates," Dr. Shann writes. "G-CSF and GM-CSF should no longer be
used routinely in neonatal intensive care without further evidence
from randomised trials. Unfortunately, funding is difficult to get
for trials of treatments that will be used in very few patients, or
that are not under patent."

Action Medical Research supported the trial. The authors and Dr.
Shann have disclosed no relevant financial relationships.

Lancet. 2009;373:188¡V190, 226¡V233.

Elderly patients hospitalized with heart failure who go on beta
blockers for the first time and continue them after discharge can
expect prolonged survival and fewer rehospitalizations, unless they
are one of the many with preserved systolic function, suggests an
analysis based on a large prospective registry [1]. The findings,
which appear in the January 13, 2009 issue of the Journal of the
American College of Cardiology, are consistent with the few other
studies of beta blockade in comparable patients and highlight how
poorly understood preserved¡Vejection-fraction heart failure is
compared with systolic heart failure.

The adjusted one-year mortality for patients in the analysis who
were discharged on beta blockers was reduced by a significant 23%
among those with systolic dysfunction but not at all, statistically,
among patients with preserved systolic function. There was also a
significant drop in readmissions on beta blockade in the former
group but not the latter. All of the >7000 patients in the analysis,
from the Organized Program to Initiate Lifesaving Treatment in
Hospitalized Patients With Heart Failure (OPTIMIZE-HF) registry, had
been eligible for beta blockade but weren't on them when
hospitalized.

The patients averaged about 80 years in age, slightly younger for
the group discharged on beta blockers.

Clearly, there is powerful evidence for significant benefit from
certain beta blockers in systolic heart failure, observed lead
author Dr Adrian F Hernandez (Duke Clinical Research Institute,
Durham, NC). But based on this analysis and some other data, he told
heartwire, beta blockers are not the answer for heart failure with
preserved systolic function--although such patients may find them
beneficial if they also have diabetes, hypertension, or other
indications for the drugs.

"Certainly our findings are disappointing and, on the heels of I-
PRESERVE, clearly demonstrate that for half the population with
heart failure, we need, one, to understand more about their
pathophysiology, and two, to develop different targets for their
treatment," according to Hernandez.

The I-PRESERVE trial, as recently reported by heartwire, found no
effect on mortality or CV events from the angiotensin-receptor
blocker irbesartan (Avapro, Bristol-Myers Squibb/Sanofi-Synthelabo)
over a four-year follow-up of patients with heart failure and
preserved systolic function.

Such patients typically account for about half of all heart failure
in most reports. In the current analysis, they represented closer to
60%. Systolic dysfunction was defined as an LVEF <40% or qualitative
documentation of systolic dysfunction, while preserved systolic
function meant LVEF >40% or qualitative documentation of preserved
systolic function.

Importantly, the analysis also underscores the poor prognosis faced
by preserved¡Vsystolic-function heart-failure patients, according to
Hernandez. Their one-year mortality was about 32%, and
rehospitalization rate was about 65%. "They're still the elephant in
the room. We still don't know what to do with them."

The ongoing, government-funded Treatment of Preserved-Cardiac-
Function Heart Failure (TOPCAT) trial, Hernandez observed, is
exploring whether the aldosterone inhibitor spironolactone will
improve their outcomes.

The study was supported by GlaxoSmithKline.


Hernandez AF, Hammill BG, O'Connor CM, et al. Clinical effectiveness
of beta-blockers in heart failure. Findings from the OPTIMIZE-HF
(Organized Program to Initiate Lifesaving Treatment in Hospitalized
Patients With Heart Failure) registry. J Am Coll Cardiol 2009;
53:184-192).

More evidence is available supporting the preemptive use of statins
in patients undergoing cardiac surgery, only this time the benefit
extends to patients without existing coronary artery disease [1].

A new retrospective review, published in the December 2008 issue of
the Journal of Thoracic and Cardiovascular Surgery, has shown that
the preoperative use of statins is associated with lower mortality
among patients undergoing valve surgery.

"Clinically, this study implies that a preemptive use of
preoperative statins may improve operative outcomes in patients
undergoing cardiac valve surgery who do not have a history of
coronary artery disease," write lead investigator Dr Minoru Tabata
(Brigham and Women's Hospital, Boston, MA) and colleagues. "Our
cohort includes concomitant aortic, congenital, and other cardiac
procedures. Combined with previous findings in coronary artery
bypass graft and patients with coronary artery disease, the
beneficial effects of preoperative statins may be generalizable to
most patients undergoing cardiac surgery."

Patients Without a History of Coronary Artery Disease

The use of preoperative statin therapy among patients undergoing
CABG surgery has been shown to improve operative outcomes in other
studies, including a large 30 000-patient meta-analysis published in
the June 2008 issue of the European Heart Journal [2]. In that
study, previously reported by heartwire, preoperative statins
reduced the risk of 30-day mortality from any cause by 40%, as well
as significantly reduced the risk of stroke and atrial fibrillation.

As Tabata and colleagues point out, however, the role for
preoperative statins in patients without coronary artery disease is
less defined.

In this review, the investigators analyzed data from 1389 patients
undergoing cardiac valve surgery, excluding those undergoing
concomitant CABG surgery and those with a history of MI. Of these
patients, 363 were treated with a statin, including 197 who were
taking atorvastatin and 126 who were taking simvastatin. More than
half of the atorvastatin patients were taking the 10-mg dose,
whereas most simvastatin patients were taking either the 20-mg or 40-
mg dose.

Patients pretreated with statins prior to surgery had a lower rate
of operative mortality--defined as death within 30 days after
surgery--than those not taking statins. The rate of death was 0.8%
among the statin-treated patients compared with 2.3% for the non¡V
statin-treated group, a difference that translated into a 75% lower
risk of death within 30 days. Statin pretreatment had no effect on
the risk of stroke or perioperative MI rates.

The pleiotropic effects of statins, including improved endothelial
function, enhanced stability of atherosclerotic plaque, decreased
oxidative stress and inflammation, and an inhibited thrombogenic
response are possible biological mechanisms underlying the
beneficial effect, suggest the authors.

"These effects may attenuate the proinflammatory effects of surgical
invasiveness and cardiopulmonary bypass," write Tabata and
colleagues. Further study, however, is needed to confirm the
benefit, as well as to confirm the biological mechanism providing
the reduction in mortality, they add.

Statin Pretreatment Reduces Myocardial Damage

Another study, also appearing in the December 2008 issue of the
Journal of Thoracic and Cardiovascular Surgery, has shown that
pretreatment with statins, specifically rosuvastatin (Crestor,
AstraZeneca), reduces myocardial damage following cardiac surgery
[3].

In total, 200 patients, including those with coronary artery
disease, were randomized to rosuvastatin 20 mg or placebo one week
before coronary surgery. Troponin I, myoglobin, and creatine kinase-
MB mass levels--all markers of myocardial injury--were lower after
surgery among patients pretreated with rosuvastatin. High-
sensitivity C-reactive protein (hs-CRP) levels were also
significantly less elevated; CRP increased 58% in the pretreated
statin-therapy arm and 88% in those randomized to placebo.

In their paper, lead investigator Dr Vito Mannacio (University of
Naples Federico II, Italy) and colleagues point out that large event-
driven studies are needed to assess the advantages of preoperative
statin therapy and that other populations, including those with
diabetes, unstable patients, and patients with extensive coronary
artery disease and decreased left ventricular function, need to be
included in future trials.


Tabata M, Khalpey Z, Cohn LH, et al. Effect of preoperative statins
in patients without coronary artery disease who undergo cardiac
surgery. J Thorac Cardiovasc Surg 2008: 136: 1510-1513. Abstract
Liakopoulos OJ, Choi YH, Haldenwang PL, et al. Impact of
preoperative statin therapy on adverse postoperative outcomes in
patients undergoing cardiac surgery: a meta-analysis of over 30 000
patients. Eur Heart Journal 2008; 29:1548-1559. Abstract
Mannacio V, Iorio D, De Amicis V, et al. Effect of rosuvastatin
pretreatment on myocardial damage after coronary surgery. J Thorac
Cardiovasc Surg 2008: 136:1541-1548. Abstract

A new study suggests that between 1998 and 1999, Medicare managed-
care plans did not have a positive effect on the appropriate use of
carotid endarterectomy (CEA) or outcomes, failing to deliver on
their promise, the researchers say.

"We were surprised that Medicare patients with managed-care
insurance didn't seem to have any benefit as far as lower rates of
overuse of carotid surgery or better outcomes, and in fact, it
looked like they were less likely to be referred to high-volume
providers," lead author Ethan A. Halm, MD, from the Mount Sinai
School of Medicine, in New York, told Medscape Neurology &
Neurosurgery.

"The managed-care plans had the motive, the means, and the
opportunity to try to prevent overuse and selectively refer to high-
quality providers, but they didn't do it," he said.

Their analysis appears in the December issue of the American Journal
of Medical Quality.

CEA a Good Marker

Managed care became the dominant form of healthcare insurance during
the 1990s, with advocates saying that these organizations would
improve quality of care and outcomes while reducing costs. The
improvements would be obtained by, among other interventions,
precertifying elective procedures for their appropriateness and
selective referral of patients to high-quality doctors and
hospitals.

In this analysis, Dr. Halm and colleagues looked to see whether the
promise of managed care had been fulfilled by focusing on its effect
on the use of CEA among Medicare beneficiaries in New York State
between January 1, 1998 and June 30, 1999.

"One of the reasons that we thought this was a good procedure to
look at the impact of managed care is that there have been
randomized, controlled trials outlining who benefits and in what
situations for carotid surgery that have been published for years,
and both the American Heart Association and the American Stroke
Association had set guidelines on what is considered appropriate or
inappropriate patients to have carotid surgery," Dr. Halm said.

In addition, it is "widely known" that high-volume surgeons and
hospitals have better outcomes for carotid surgery, and the managed-
care plans would have access to this information, he pointed out.

In the current study, the researchers looked at whether Medicare
patients who were enrolled in Medicare Choice (MC) managed care
plans (the precursor to Medicare's current MC plans) had lower rates
of inappropriate CEA, had their operations performed more frequently
by high-volume surgeons or hospitals, or had better perioperative
outcomes than those enrolled in fee-for-service (FFS) plans.

Clinical data were abstracted from medical records for 8691 FFS
patients and 897 MC patients undergoing CEA to assess
appropriateness and outcomes, including death and stroke within 30
days of surgery. Patients in both groups had similar indications for
surgery, perioperative risk, and comorbidities, they note.

In the end, there were no differences in inappropriateness between
FFS and MC patients, and MC patients were in fact less likely to be
referred to either a high-volume surgeon or a high-volume hospital
than FFS patients (P < .05).

Nor were there differences between groups in risk-adjusted rates of
death or stroke (OR 0.97; 95% CI, 0.69 ¡V 1.37).

Because CEA is always elective and there are good published data
upon which to make informed decisions, the conclusion must be that
these plans did not, for whatever reason, avail themselves of them,
Dr. Halm said. "This is something they were really set up to do,
that they had access to do, and they just failed to do it."


The researchers also carried out a follow-up survey of plan medical
directors to see whether they had missed plans that were actively
trying to use evidence-based criteria to send patients to high-
quality providers or prevent overuse through utilization-review
mechanisms. "None of them had any procedure-specific utilization
review guidelines they were using," he added.

Instead, he noted, "they seemed largely to be focusing on
contracting based on negotiated cost, not really based on either the
quality of the docs or the hospitals that were delivering the care.
Unfortunately, even though they had financial incentives to prevent
overuse of inappropriate care, they weren't using the second
utilization review mechanism actually set up to do that in a
structured or guideline-driven way."

"Managed Care Lite"


"It's worth saying that this time period represents close to the
apex of managed care's intrusiveness and choice restriction, when
the managed-care backlash was happening," Dr. Halm added. "This
wasn't a test of the 'managed care lite' that we have now, so if
they would have been able to do something, they should have been
doing it back then, but they didn't."

They plan to do some further analyses in this area, he said. "One is
to try to come up with an algorithm that will help neurologists,
surgeons, and referring docs to evaluate which patients are the best
candidates for carotid surgery and to help individualize the short-
term risk of complications for a given patient to help inform
decisions about who should go to surgery and who might be too high
risk."

They are also looking at differences by race in outcomes and
appropriateness, he noted.

The study was supported by the Agency for Healthcare Research and
Quality, the Center for Medicare and Medicaid Services, and by the
Robert Wood Johnson Foundation.

Am J Med Qual. 2008;23:448-456. Abstract

The medical treatment of inoperable chronic thromboembolic pulmonary
hypertension (CTEPH) looks set to be confined to off-label therapy
for the foreseeable future, because the only rigorously conducted
trial of any drug in this specific indication has failed to show a
clear benefit [1].

That trial--Bosentan Effects in Inoperable Forms of Chronic
Thromboembolic Pulmonary Hypertension (BENEFIT)--conducted with the
dual endothelin antagonist bosentan (Tracleer, Actelion
Pharmaceuticals), produced mixed results, with a positive treatment
effect of bosentan on hemodynamics but no improvement in exercise
capacity. The BENEFIT results were first reported at the European
Society of Cardiology (ESC) meeting in Vienna in 2007 and appear in
the December 16, 2008 issue of the Journal of the American College
of Cardiology, by Dr Xavier Jais (Antoine Beclere Hospital, Clamart,
France) and colleagues.

Coauthor Dr Irene M Lang (Medical University of Vienna, Austria),
told heartwire that the published results do not differ from those
she presented at the ESC meeting, but she believes they could be
sufficient for bosentan to be approved for CTEPH. However, the
drug's manufacturer told heartwire it has no plans to pursue an
approval for this indication.

Inoperable CTEPH: A Chronic, Devastating Disease

CTEPH is a form of pulmonary hypertension (PH); PH affects more than
2.5 million people worldwide and is characterized by hypertension in
the pulmonary artery, vein, or capillaries, leading to shortness of
breath, dizziness, fainting, and other symptoms, all of which are
worsened by exertion and can lead to markedly decreased exercise
tolerance, heart failure, and death. The only approved therapies
currently available are for a different form of PH, pulmonary
arterial hypertension, which comprises only a small proportion of PH
cases, so the majority of patients are without approved treatment.

When the BENEFIT results were reported at the ESC meeting, the
discussant, Dr Nazzareno Galie (University of Bologna, Italy), said
this was the first time a randomized controlled study has shown
favorable hemodynamic effects of a targeted therapy in this group of
patients (inoperable CTEPH), but he noted the obvious discrepancy: a
clear decrease in pulmonary vascular resistance was demonstrated,
but there was no change in six-minute walking distance.

Lang told heartwire: "Some people think there is a signal there and
that [bosentan] should be approved for inoperable CTEPH because
there is a bad need for medical treatments for this indication. This
is a chronic, very devastating disease that hits elderly people, and
it's an important problem."

Was the Follow-Up Too Short in BENEFIT?

There are a couple of possible explanations for the discrepancies in
BENEFIT, Galie said in Vienna. First, CTEPH patients are older and
have more comorbidities than patients with PAH, in whom bosentan is
already approved. In addition, the short duration of the study--just
three months of follow-up--may have played a role, he said,
explaining that improvements in exercise capacity can sometimes take
as long as a year to manifest.

Lang takes this up, explaining to heartwire that there is to be
a "statistical look" at the open-label phase of the BENEFIT trial,
but that she does not yet know the results of this phase. She added
that she was not sure whether Actelion Pharmaceuticals would file
for approval of bosentan for inoperable CTEPH on the basis of
BENEFIT, stating that this is a matter "of some debate."

However company spokesperson Roland Haefeli, vice president for
investor relations and public affairs, told heartwire: "In terms of
[inoperable] CTEPH, we currently have no plans for regulatory
proceedings [with bosentan]."

Much Off-Label Use of Bosentan, Sildenafil

Lang told heartwire that whether or not bosentan is actually
approved for inoperable CTEPH, the drug would still be used for this
indication. "I estimate that around 60% of patients with inoperable
CTEPH are treated medically off-label, mainly with sildenafil and
bosentan, which is a very bad situation," she said.

In many countries, sildenafil is the preferred option, she added,
because it is available generically and therefore considerably
cheaper than bosentan. Sildenafil, a phosphodiesterase inhibitor
best known as the erectile-dysfunction therapy Viagra, is approved
for PAH as Revatio (Pfizer). Lang added that there has never been an
appropriately powered trial to assess sildenafil for the CTEPH
indication, "but it appears to do something."

Another new drug is also being investigated for inoperable CTEPH as
well as other forms of PH, she adds. Bayer's riociguat, a soluble
guanylate cyclase stimulator, is about to begin two phase 3 trials:
one in CTEPH and the other in PAH [2]. And phase 2 studies of
riociguat are under way in patients suffering from other forms of PH.

The BENEFIT trial was funded by Actelion Pharmaceuticals. Lang
reports receiving honoraria from Actelion, Bayer-Schering, Pfizer,
AstraZeneca, GlaxoSmithKline, AOP Orphan Pharmaceuticals, the
European Union, and the Austrian government. Disclosures for other
BENEFIT authors are listed in the paper.


Jais X, D'Armini AM, Jansa P, et al. Bosentan for treatment of
inoperable chronic thromboembolic pulmonary hypertension. BENEFIT
(bosentan effects in inoperable forms of chronic thromboembolic
pulmonary hypertension) a randomized, placebo-controlled trial. J Am
Coll Cardiol 2008; 52:2127-2134. Abstract
Bayer Schering Pharma. Bayer reports progress in clinical program
for riociguat [press release]. October 6, 2008. Available at:
http://www.press.bayer.com/baynews/baynews.nsf/id/A2F9D590C44A5879C12
574DA001A936C?Open.

The risk of new-onset atrial fibrillation went up sharply with
increasing resting heart rate in patients receiving drug therapy for
hypertension in the Losartan Intervention for End Point Reduction in
Hypertension (LIFE) study, report investigators in the December 2008
issue of Circulation: Arrhythmia and Electrophysiology [1].

The LIFE analysis of 8828 hypertensive patients with LV hypertrophy
(by electrocardiography) but without a history of AF tracked heart
rate at baseline, six months, and then annually over an average of
almost five years. Each 10-bpm increment in heart rate corresponded
to a 19% increased risk of incident AF. The risk of "persistence or
development" of AF was increased by 61% in patients with heart rates
in the highest quintile, that is, >84 bpm, according to Dr Peter M
Okin (Weill Medical College of Cornell University, New York, NY) and
associates.

The link between heart rate and incident AF was independent of
antihypertensive therapy group, the blood-pressure-lowering effect
of treatment, and comorbidities. It was also independent of the anti-
AF effects both losartan itself and regression of LV hypertrophy
separately demonstrated in prior LIFE subanalyses, as previously
reported by heartwire.

"People who have higher-than-normal resting heart rates are at
increased risk of developing atrial fibrillation and deserve further
investigation to determine whether there are underlying preventable
abnormalities that are worth looking into," according to Okin. Heart
rates that go up over time should also be investigated, he said to
heartwire.

In such cases, when the patient doesn't have other obvious
conditions that can raise heart rate, like infections or acute
illness, Okin said, "physicians should take a step back and ask, why
is this happening? Heart rates go up for a reason. What else is
going on that's putting the patient at risk?"

According to the LIFE trial's primary outcomes, reported in 2002 [2]
and covered at the time by heartwire, blood pressure dropped
similarly for patients randomized to antihypertensive therapy based
on either losartan or atenolol, while the losartan group showed a
significantly decreased risk of the composite primary end point
(p=0.021), consisting of death, MI, or stroke. The 12% reduced risk
was driven predominantly by a 25% reduced risk of fatal or nonfatal
stroke (p=0.001). A subsequent analysis suggested that the risk of
incident AF and the risk of stroke among patients with AF were
significantly lower among patients who received losartan.

"The relationship between heart rate and outcomes is convincing,"
notes an accompanying editorial [3] about the current study. Dr
Rakesh Gopinathannair (University of Iowa, Iowa City) and associates
acknowledge that it was conducted post hoc and so has inherent
limitations but that "use of multiple statistical tools makes the
analysis robust."

"This novel work," write the editorialists, "has the potential to
influence drug therapy in hypertensive patients as part of an effort
to prevent atrial fibrillation. The question, however, remains as to
whether heart rate is really a modifiable risk factor." Faster heart
rates may imply more comorbidities that themselves increase the risk
of AF, or it may be that hypertension, faster heart rate, and AF
share common neurohormonal underpinnings. "The mechanisms by which
hypertension leads to atrial fibrillation and the relation between
atrial pressure, stretch, and autonomic shifts in patients who
develop atrial fibrillation remain areas of active investigation."

The LIFE trial was supported by Merck. Coauthors Darcy A Hille and
Dr Jonathan M Edelman are Merck employees "and may own stock or hold
stock options" in the company. Principal editorialist Dr Brian
Olshansky (University of Iowa) reports receiving honoraria for
speaking and funding for research and having consulted for Boston
Scientific, Medtronic, St Jude Medical, Novartis, Sanofi-Aventis,
Roche, Baxter, GlaxoSmithKline, Reliant, and Biocontrol.

Sources


Okin PM, Wachtell K, Kjeldsen SE, et al. Incidence of atrial
fibrillation in relation to changing heart rate over time in
hypertensive patients: the LIFE study. Circ Arrhythmia
Electrophysiol 2008; 1:337–343.
Dahlöf B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity
and mortality in the Losartan Intervention for End point reduction
in hypertension study (LIFE): a randomised trial against atenolol.
Lancet 2002; 359:995-1003.
Gopinathannair R; Sullivan RM; Olshansky B. Slower heart rates for
healthy hearts. Time to redefine tachycardia? Circ Arrhythmia
Electrophysiol 2008; 1:321-323.

Acute-MI patients who possess the genetic variant linked previously
with variability in the antiplatelet response to clopidogrel
(Plavix, Bristol-Myers Squibb/Sanofi-Aventis) are at an increased
risk of death, recurrent MI, and urgent coronary revascularization
when placed long-term on the antiplatelet regimen [1].

"Our study shows a strong relation between the presence of the
CYP2C19*2 allelic variant and recurrent thrombotic coronary events
in clopidogrel-treated patients predominantly of European ancestry
who survived a myocardial infarction before 45 years of age," write
lead investigator Dr Jean-Philippe Collet (INSERM, Paris, France)
and colleagues in a paper published online December 23, 2008 in the
Lancet.

In their paper, the group explains that variability in the gene that
encodes the cytochrome P450 2C19 enzyme is thought to contribute to
the effectiveness of clopidogrel as an antiplatelet agent. This
enzyme is active in the biochemical pathway that converts
clopidogrel into an active metabolite, and the loss-of-function
polymorphism, known as CYP2C19*2, is associated with reduced
clopidogrel responsiveness.

In addition to this study, Dr Tabassome Simon (Université Pierre et
Marie Curie, Paris, France) and colleagues also examine the
subsequent risk of cardiovascular events among acute-MI patients
with the CYP2C19 alleles receiving clopidogrel [2].

Publishing findings from the French Registry of Acute ST-Segment
Elevation and Non-ST-elevation Myocardial Infarction (FAST-MI) study
online December 22, 2008 in the New England Journal of Medicine, the
investigators show that patients carrying any two of the CYP2C19
loss-of-function alleles, which included CYP2C19*2, CYP2C19*3,
CYP2C19*4, or CYP2C19*5, were at a significantly greater risk of
death, MI, or stroke.

A third study, from the Thrombolysis in Myocardial Infarction (TIMI)
study group, showed that, among clopidogrel-treated subjects,
carriers of the reduced-function CYP2C19 alleles had a more than 50%
increased risk in the primary end point of death from cardiovascular
causes, MI, or stroke, when compared with noncarriers, as well as a
threefold increase in the risk of stent thrombosis [3].

Speaking with heartwire, Dr Eric Topol (Scripps Translational
Science Institute, La Jolla, CA), who was not part of any of the
studies, called the results "major findings in cardiovascular
medicine," especially since clopidogrel is the second-most-
prescribed drug in the world.

"At this moment in time in cardiovascular medicine, this is perhaps
the most striking, practical, pharmacogenetic relationship
demonstrated," said Topol. "It has practical implications for
managing patients and for patients getting a stent and clopidogrel.
At least one-third, if not more, depending on ancestry, are at
considerably higher risk for stent thrombosis, and this information
isn't being taken into account."

The CYP2C19 variant is extremely common, occurring in 30% of
individuals of European ancestry, 40% of individuals of African
ancestry, and in more than 50% of individuals of Asian ancestry,
noted Topol.

Loss-of-Function Alleles and Clopidogrel Resistance

In the FAST-MI paper, Simon and colleagues report their findings
based on data from 2208 patients with an acute MI treated with
clopidogrel. In addition to CYP2C19, the researchers also assessed
the relationship between variants of genes modulating clopidogrel
absorption, such as ABCB1, as well as genes modulating metabolic
activation and biologic activity, and the risk of cardiovascular
events during one year of follow-up.

During the follow-up period, there were 225 deaths and 94 nonfatal
MIs or strokes. Patients with two variant alleles of ABCB1 had a
significantly greater risk of death from any cause, nonfatal stroke,
or MI at one year compared with individuals with the ABCB1 wild-type
genotype.

Among patients carrying any two variants of CYP2C19, there was a
doubling in the risk of cardiovascular events at one year compared
with individuals without any of the loss-of-function alleles.

This increased risk was even more pronounced among those who
underwent PCI during hospitalization. Among these 1535 PCI patients,
the rate of cardiovascular events among those with two CYP2C19 loss-
of-function alleles was 3.5 times greater than among those without
the genetic polymorphism.

Analysis From TRITON-TIMI-38

The TIMI study group also gets in on the clopidogrel-genetics action
in the study by Dr Jessica Mega (Brigham and Women's Hospital,
Boston, MA), which is also published online December 22, 2008 in the
New England Journal of Medicine.

In an analysis of the Trial to Assess Improvement in Therapeutic
Outcomes by Optimizing Platelet Inhibition with Prasugrel (TRITON–
TIMI) 38, the researchers tested the association between functional
genetic variants in cytochrome P450 genes, plasma concentrations of
active drug metabolite, and platelet inhibition in response to
clopidogrel in 162 healthy subjects.

Carriers of at least one CYP2C19 loss-of-function allele had a 30%
relative reduction in plasma exposure to the active metabolite of
clopidogrel when compared with noncarriers. In addition, these
carriers also had a significant 9% absolute reduction in maximal
platelet aggregation in response to clopidogrel.

In terms of cardiovascular outcomes among clopidogrel-treated
subjects, carriers had a more than 50% increased risk in the primary
end point of death from cardiovascular causes, MI, or stroke
compared with noncarriers, as well as a threefold increase in the
risk of stent thrombosis.

Lancet Study Also Published

In the Lancet study, the researchers assessed whether the CYP2C19*2
polymorphism is associated with clinical outcomes of acute-MI
patients treated long-term with clopidogrel. Using data from the
large Appraisal of Risk Factors in Young Ischemic Patients
Justifying Aggressive Intervention (AFIJI) registry, they identified
259 patients younger than 45 years who survived a first MI and were
exposed to clopidogrel for at least one month. All patients
underwent genetic testing for the CYP2C19*2 polymorphism.

After a median exposure of 1.07 years, the primary end point, a
composite of death, nonfatal MI, and urgent revascularization,
occurred more frequently in carriers vs noncarriers of CYP2C19*2. In
total, there were 11 events in individuals without the CYP2C19*2
allele and 15 events in those heterozygous and homozygous for
CYP2C19*2.

"The magnitude of the detrimental effect of the CYP2C19*2 genetic
variant was unexpected in view of the clinical benefits that were
recorded with clopidogrel in previous studies that used similar
clinical end points," write Collet and colleagues.

The group notes that at the last follow-up visit, 213 patients were
still receiving a maintenance dose of 75 mg per day of clopidogrel,
and nearly all of these were receiving low-dose aspirin in
combination. They note that it is unknown whether higher doses of
clopidogrel would override the detrimental effect of the loss-of-
function CYP2C19*2 polymorphism, but this warrants further
investigation.

Speaking with heartwire, Topol noted there are inconsistencies
across the three studies, mainly in that the TRITON-TIMI-38 analysis
and the study by Collet and colleagues documented a higher risk of
cardiovascular events among carriers, with threefold and sixfold
increases in the risk of stent thrombosis, respectively.

In contrast, carriers of the gene included in the FAST-MI analysis
appeared to be at lower risk. "It's a very peculiar finding," said
Topol.

Overall, however, Topol said the findings, taken together to include
ABCB1 and CYP2C19, as well as the reduced-function CYP2B6 allele
that appears to affect the amount of active metabolite in the TRITON-
TIMI analysis, suggest that multiple genes are at work.

"There are other things lurking besides this very important CYP2C19,
and probably with larger samples and more events you'd have enough
power to pick up CYP2B6 and further demonstrate the importance of
ABCB1," said Topol.

The findings also need to be independently replicated before being
extrapolated to older patients or those of non-European ancestry,
write Collet and colleagues. The results, however, raise the
question of whether or not the prognostic information associated
with the CYP2C19*2 genotype can be used to guide management of these
patients.

In an editorial accompanying the Lancet study [4], Dr Robert Storey
(University of Sheffield, UK) called the degree of risk associated
with the variant "remarkable," partly because the conversion of
clopidogrel to its active metabolite can be achieved through several
cytochrome P450 enzymes. Other mechanisms should be explored and
further testing carried out to determine whether having the
CYP2C19*2 variant is associated with other genetic determinants of
risk, he writes.

Regarding the possibility of genotyping patients with acute coronary
syndrome to identify CYP2C19*2 carriers for risk stratification,
Storey believes the concept is attractive, but several factors are
likely to dampen enthusiasm. "The results of such an analysis would
be unlikely to be available at the time of starting clopidogrel and
during the high-risk phases of an acute coronary syndrome," he
writes. Other drugs, he notes, including prasugrel, are currently in
development and could potentially provide solutions to the problems
of variability in the response to clopidogrel.

Regarding genotyping patients to identify the CYP2C19 variant, Topol
said he thinks genotyping could be incorporated into daily practice.
If two million patients are getting stents annually, then some 700
000 individuals are at increased for stent thrombosis based on their
genetics.

Sources


Collet JP, Hulot JS, Pena A, et al. Cytochrome P450 2C19
polymorphism in young patients treated with clopidogrel after
myocardial infarction: a cohort study. Lancet 2008;
DOI:10.1016/S0140-6736(08)61845-0. Available at:
http://www.thelancet.com.
Simon T, Verstuyft C, Mary-Krause M, et al. Genetic determinants of
response to clopidogrel and cardiovascular events. N Engl J Med
2009; DOI 10.1056/NEJMoa0808227. Available at: http//www.nejm.org.
Mega JL, Close SL, Wiviott SD, et al. Cytochrome P-450 polymorphisms
and response to clopidogrel. N Engl J Med 2009; DOI:
10.1056/NEJMoa0809171. Available at: http://www.nejm.org.
Storey R. Clopidogrel in acute coronary syndrome: to genotype or
not? Lancet 2008; DOI:10.1016/S0140-6736(08)61846-2. Available at:
http://www.thelancet.com.

Therapeutic instead of prophylactic platelet transfusions are safe,
feasible, and would reduce costs considerably, say German
researchers reporting the first worldwide randomized study comparing
the 2 different strategies. However, the study was conducted in 171
patients, and experts believe more data are needed before
conclusions can be drawn about safety and the new strategy is
implemented.

The trial was presented here at the American Society of Hematology
(ASH) 50th Annual Meeting and Exposition by Hannes Wandt, MD, from
the Klinikum Nuremberg Nord, in Nuremberg, Germany. It was conducted
in patients who had recently received high-dose chemotherapy, total-
body irradiation, or autologous stem-cell transplant for a variety
of hematological malignancies, including multiple myeloma, non-
Hodgkin's lymphoma, Hodgkin's disease, and acute myeloid leukemia.

Such patients often become thrombocytopenic. Current practice is to
treat patients with prophylactic platelet transfusions, which are
triggered when the platelet count falls below 10,000/uL. Dr. Wandt
and colleagues compared this standard practice to an experimental
strategy of therapeutic platelet transfusions, where patients
received a transfusion only when they experienced a clinically
relevant bleed (more than petechias or minimal mucosal bleeding).

This new strategy significantly reduced the number of platelet
transfusions that were administered ¡X from 152 in the prophylactic
group to 118 in the therapeutic group, a reduction of 27% (P
= .004). There were 14 instances in the prophylactic group where the
trigger was reached but a transfusion was not given; if these are
included, the reduction is even greater (33%), Dr. Wandt reported.

In addition, with the therapeutic strategy, 46% of patients did not
need a platelet transfusion, which is nearly double the 22% in the
prophylactic group, Dr. Wandt commented.

The reduction in platelet transfusions seen in the therapeutic group
of this study could translate into huge cost savings. Dr. Wandt
estimated that if this strategy was implemented only for patients
who receive autologous transplants, based on figures from official
registries of such patients in the United States and Europe, an
estimated 16,460 apheresis platelet units could be saved each year.
This translates to cost savings of £á8 million or $10 million to $11
million each year.

More Bleeding Episodes in Therapeutic Group

There were more instances of clinically relevant bleeding in the
therapeutic group than in the prophylactic group (37% vs 7%),
although this is to be expected with a strategy that has bleeding as
the trigger for transfusion, Dr. Wandt commented. "All of the
bleeding events were of minor to moderate severity (grade 2 or 3)
and were safely treated with transfusions," he said.

"It is clear that bleeding episodes are increased, but these are
triggers for transfusion, and if you follow this strategy, you have
to accept this," Dr. Wandt commented. However, there were no severe
or fatal bleeds, he added.

There was no difference between the 2 groups in hospitalization,
number of red-blood-cell units transfused, or leukocytopenia. In
contrast, the duration of thrombocytopenia (platelet count of ≤
20,000/uL) was significantly longer in the therapeutic-transfusion
group than in the prophylactic group (median of 5 days vs 3 days; P
= .004), as would be expected with this strategy, Dr. Wandt
commented.

"We conclude that our therapeutic platelet-transfusion strategy is
cost effective and safe in patients after autologous stem-cell
transplantation," Dr. Wandt told the meeting. Despite more minor
hemorrhages with the experimental strategy than with the traditional
prophylactic strategy, all bleeding events could be safely
controlled by consecutive platelet transfusion, and development of
major bleeding could be prevented, he added.

However, several clinicians in the audience took issue with the
conclusion that this strategy was safe, saying that the patient
numbers were too small to detect a difference in severe bleeding
between the 2 groups.

Dr. Wandt countered by emphasizing that no major life-threatening
bleeds were seen in this study, nor in a previous study that his
group conducted in 140 patients with autologous stem-cell
transplants (Bone Marrow Transplant. 2006;37;387-392). His group is
currently conducting a similar randomized trial in patients with
acute myeloid leukemia, so more data will be available soon.

But he did acknowledge that the patient numbers so far may be too
small to detect a difference in severe bleeds, and he pointed out
that such a difference may be extremely small. His group previously
calculated that to detect such a difference, a clinical trial would
need to have 2000 patients in each group.

Asked to comment on this therapeutic platelet-transfusion strategy,
current ASH president Kenneth Kaushansky, MD, professor of medicine
at the University of California, San Diego, said that this was
interesting but it was too early to change clinical practice. "We
need more data," he said.

Sherrill Slichter, MD, an expert on platelet transfusions from the
Puget Sound Blood Center, in Seattle, Washington, agreed that more
data are needed, particularly in different patient populations. The
group for which there are the most data is autologous transplants
and, in her experience, this subgroup has a lower incidence of
bleeding than other groups. She noted that in the PLADO study that
she presented at the meeting, already reported by Medscape Oncology,
patients who received autologous transplants had a 54% rate of
bleeding, compared with 68% in patients who received chemotherapy,
and 72% in patients who received an allogeneic transplant. She said
it will be interesting to see results from the ongoing study in
acute myeloid leukemia patients, which Dr. Wandt hopes to present at
the ASH meeting next year.

In the decision as to whether to replace an implantable cardioverter
defibrillator (ICD) that has become subject to a safety advisory,
the guiding equation is more likely to be "risk vs risk" than risk
vs benefit. The potential hazards of leaving a device in depend on
the safety issue and can be apparent, the risks inherent to device
replacement may be less well defined, and knowing what can promote
them would presumably inform the decision.

In a retrospective experience from a dozen major device-implantation
centers across Canada [1], published in the December 2008 issue of
Heart Rhythm, advisory-ICD-replacement complication rates were in
line with prior studies of the issue and complication risk factors
included some that make perfect sense but at least one that was
unexpected.

One message from the case-control study, according to principal
coauthor Dr Andrew D Krahn (London Health Sciences Centre, ON), is
that ICD-generator replacements are not as easy as often
perceived. "From a surgical perspective, this is a really, really
simple operation. It may feel like nothing can go wrong when it
takes you 20 minutes and by the time you're done it feels like
you've barely started," he told heartwire.

"Whereas when you have to address lead issues, it¡¦s a more involved
procedure, and the mind connects that with more to go wrong."

But, he said, the risks of generator replacement appear to be on the
same order of magnitude.

Krahn said the rates he usually cites for lead extraction are about
2% for major complications and 0.5% for death. In the current
analysis of 451 patients with advisory-ICD replacement followed for
a year, 6.0% developed major complications; the rate included a
0.44% mortality. Major complications were defined as death, nonfatal
MI, cardiogenic shock, or reoperation due to hematomas, infections,
malfunctions, or significant pain.

Pocket infections requiring device extraction accounted for more
than a third of the major complications and were involved in both of
the deaths.

The major-complication rate compares with the 5.8% rate for advisory-
ICD replacements over a mean of 2.7 months at 17 Canadian centers
reported by many of the same coauthors in a 2006 issue of the
Journal of the American Medical Association [2].

In the current analysis, the rate of minor complications was 3.1%;
they consisted entirely of medically managed pain or incisional
infection and postoperative exacerbation of a medical condition.

As noted in the report, with first author Dr Paul A Gould
(University of Western Ontario, London), "Data from our current
study suggest that ICD-generator advisories are potentially as
complex to intervene on as advisories with ICD leads."

In an accompanying editorial, Dr Mark H Schoenfeld (Yale University,
New Haven, CT) makes the point with even greater urgency [3]. "What
is clear from this study, and all too often underappreciated, is
that there is no such thing as a 'minor' procedure, and that
replacing a device under advisory cannot be considered 'just' a
generator replacement."

In a case-control analysis that looked for independent risk
predictors, the 41 patients who suffered complications were matched
by age and sex with 82 patients in whom advisory ICDs were safely
replaced.

From among a long list of potential risk factors, two emerged as
independently significant in multivariate analysis. The risk of
complications more than doubled for every procedure previously
performed on the same pocket (odds ratio 2.53 [95% CI 1.14¡V5.62];
p=0.022).

That makes sense, according to Krahn. "When patients have a
pacemaker or ICD put in for the first time, infection is quite
unusual. When they come in to have a device or lead replaced, or
anything that involves going back into a scarred area, that's when
infections are more likely to happen." Their data, he said, suggest
that multiple procedures up the risk of complications in general.

Also, surprisingly, according to Krahn, the safest advisory-device
replacements apparently were performed by two operators, generally a
fellow working with a more experienced physician.

"This is an operation that relatively junior people do without a
great deal of supervision because it's so simple, usually," Krahn
said, "and yet having two people present is associated with a little
lower risk." The difference in the analysis could have been by
chance, he said, "but the other possibility is that there's
something about two people keeping an eye on each other that makes
them that much more vigilant or fastidious."

According to the editorial, "Whether enhanced vigilance explains
the 'protective' effect of replacement procedures performed by two
operators . . . is unclear. . . . What we do know is that there is
an inverse correlation between patient outcomes and the volume of
ICD-implantation procedures performed by a physician, and that has
not been reflected in the present study."


Gould PA, Gula LJ, Champagne J, et al. Outcome of advisory
implantable cardioverter-defibrillator replacement: 1-year follow-
up. Heart Rhythm 2008; DOI:10.1016/j.hrthm.2008.09.020. Available
at: http://www.heartrhythmjournal.com.
Gould PA, Krahn AD, for the Canadian Heart Rhythm Society Working
Group on Device Advisories. Complications associated with
implantable cardioverter-defibrillator replacement in response to
device advisories. JAMA 2006; 295:1907-1911. Abstract
Schoenfeld MH. The "natural" history of implantable defibrillators
under advisory. Heart Rhythm 2008; DOI:10.1016/j.hrthm.2008.10.010.
Available at: http://www.heartrhythmjournal.com.

The advent of transvenous leads did away with thoracotomies when
putting in implantable cardioverter-defibrillator (ICD) systems,
making the procedure simpler and safer. Will the device therapy take
a similar leap forward if ICDs that use a single subcutaneous lead
become available? The availability could happen next year, according
to one of the earliest investigators of just such a device; as for
the leap, time will tell.

Currently called the subcutaneous ICD (S-ICD) by its developer,
Cameron Health (San Clemente, CA), the "active can" generator is
optimally positioned in a pocket under the arm, with the other
electrode threaded horizontally under the skin "about an inch away
from the center of the sternum," Dr Andrew Grace (Papworth Hospital
NHS Trust, Cambridge, UK) told heartwire.

The preferred pulse-generator and lead positioning and
defibrillation thresholds (DFTs) had been worked out over the past
six years or so, in some respects culminating with a small crossover
trial presented at the European Society of Cardiology Congress 2005.
As reported by heartwire at the time, 26 patients had been
randomized to be temporarily implanted with the S-ICD system first,
followed by a standard transvenous system, and 27 others received
them in the reverse order.

No fluoroscopy was allowed during S-ICD lead positioning; only
anatomic landmarks could be used, Grace had explained at the meeting
in Stockholm, Sweden.

At DFT testing, the mean effective energies for the two
configurations were 36.6 J for the S-ICD and 11.1 J for the
conventional system.

The S-ICD's greater energy requirements make for a generator that is
slightly larger than what is typical for the smallest of today's
ICDs, according to Grace. But that disadvantage may be more than
offset by the system's potential benefits. Implantation doesn't
entail doctor or patient radiation exposure, for example, and
complications related to vascular access are avoided. "We will be
able to deal with lead problems much more easily. For example, an
infection will not be systemic, it will be local," he said.

A series of about 60 patients implanted with the S-ICD is expected
to be published in early 2009, Grace said, and data from at least
that many patients will be presented to European regulators the same
year.

A new study attempting to model the future risk of coronary heart
disease (CHD) and its price, based on past and current exposure to
second-hand smoke, has found that although "passive" smoking will
continue to have a clinical and economic impact, this burden will
likely be lower than it has been in the past [1].

Dr James M Lightwood (University of California, San Francisco) and
colleagues, writing in the American Journal of Preventive Medicine,
explain that the aim of their study was to recalibrate the CHD
policy model used to predict the impact of second-hand smoke, given
that exposures have been declining over the years, in part related
to legislation limiting smoking in public spaces. Using both high
and low estimates of the relative risk of CHD associated with second-
hand smoke exposure, the authors calculated that passive smoking,
between 1999 and 2004, likely caused 21 800 to 75 100 deaths from
CHD, and 38 100 to 12 8900 MIs. Treatment costs per year ranged from
$1.8 billion to $6.0 billion, they estimated.

The revised CHD policy model used by Lightwood et al combines data
from the US Census, Framingham Heart Study (FHS), Framingham
Offspring Study (FOS), National Health and Nutrition Evaluation
Survey (NHANES), National Hospital Discharge Survey (NHDS), and
National Health Interview Survey from 2000 to create a computer
simulation of CHD incidence, prevalence, mortality, and cost among
US adults older than 35 years. From the model, the authors estimate
that active smoking declined in a linear fashion, by about 0.19
percentage points per year, from 1999 through 2008; over roughly the
same period, exposure to second-hand smoke has decreased by 25% to
40%, which has translated into a 25% to 30% reduction in the CHD
burden.

Although the reduced exposure and CHD consequences are encouraging,
Lightwood emphasizes that physicians need to keep in mind that
smoking and exposure to second-hand smoke are two of the few fully
preventable causes of death, yet people continue to smoke and be
exposed. In Lightwood et al's model, an estimated 25% to 40% of the
population aged 35 to 84 is exposed to cigarette smoke and its
inherent cardiovascular risk.

"For cardiologists, this study shows that even when you take into
account deaths from other causes, and the fact that if you survive
passive smoking sooner or later you're going to die from something,
the burden of passive smoking is still large, both in terms of
events and money spent," Lightwood told heartwire. "I would hope
that physicians and healthcare professionals in general, whether
cardiologists or not, would pay a lot of attention to this, because
depending on what group you're looking at, we still have a sizeable
population exposed to passive smoking."

He also pointed out that cardiovascular effects of smoking include
both acute and chronic effects on the heart and vasculature. "In our
literature review, we had to figure out how much passive smoking
affects heart attack and arrest, and how much is angina. How much
does it just kill you right away with a major event, and how much
does it slowly damage your arteries? And it looks like almost all of
the damage, and all of the risk, goes right to major events like
heart attack, ACS, and cardiac arrest. So there are a lot of people
who basically just keel over from this; that's where the evidence
is. So regardless of whether you're a cardiologist or not, if you're
worried about patients, passive smoking is something you're going to
want to stop."


Lightwood JM, Coxon PG, Bibbins-Domingo K, et al. Coronary heart
disease attributable to passive smoking. Am J Prev Med 2009;
DOI:10.1016/j.amepre.2008.09.030. Available at: http://www.ajpm-
online.net.

The dose of platelets given by transfusion to cancer patients who
become thrombocytopenic can be halved without increasing the risk of
bleeding, according to the results of a large study reported here at
the American Society of Hematology (ASH) 50th Annual Meeting and
Exposition. Several experts have predicted that this finding will
change clinical practice.

"We have shown that the lower dose is not adverse for the patient,"
said lead researcher Sherrill Slichter, MD, from the Puget Sound
Blood Center, in Seattle, Washington. Using fewer platelets per
transfusion would reduce the demand on the blood supply and should
also reduce costs, she said.

The PLADO study involved 1350 patients, and "the size of this trial
permits us to say that this is what we should be doing now," Dr.
Slichter commented at an official ASH press conference. "I will be
recommending that clinicians reduce the dose of platelets in
transfusions, as the risk is not there."

Current ASH president Kenneth Kaushansky, MD, professor of medicine
at the University of California, San Diego, told Medscape Oncology
that he agrees, and predicted that this trial will change clinical
practice. "Dr. Slichter is a pioneer in this area and is very well
respected. If she concludes that we can lower the dose of platelets,
then I am more than willing to go with that strategy," he said.

However, Dr. Kaushansky cautioned that "we must guard against
generalization," and emphasized that the recommendation pertains
only to patients comparable to those in the PLADO trial. Dr.
Slichter also made this point, and noted that nearly all the
participants had hematological malignancies (only 7 patients had
solid tumors), 70% had undergone bone-marrow transplants, and the
remaining 30% were treated with chemotherapy.

"This finding is important because it will decrease the utilization
of a scare resource and will also limit the exposure of patients to
blood products from donors," commented J. Evans Sadler, MD, PhD,
from the Division of Hematology at Washington University, in St.
Louis, Missouri. Dr. Sadler, who was not involved in the study, is a
cochair of the ASH Scientific Program Committee. He, too, predicted
that the results will change clinical practice.

Wait for Peer Review and Publication

"Not yet," urged Ron Strauss, MD, professor of pathology and
pediatrics at the University of Iowa Hospital, in Iowa City. "We
should continue to use the standard dose of platelets until these
results are peer reviewed and published," he commented to Medscape
Oncology, adding that conclusions are often tempered in the peer-
review process.

Dr. Strauss urged caution during an educational session. "I think it
is too risky to change practice," he said. However, Dr. Slichter
said that she disagreed, and that she felt the data were robust
enough to recommend a change in clinical practice. "It is safe based
on this study," she said.

"I am not sure," said Nancy Heddle, MSc, from McMaster University,
in Hamilton, Ontario. She also urged clinicians to wait until the
study undergoes peer review and publication before implementing
changes in clinical practice. At the same session, she presented
results from the STOP (Strategies for Transfusion of Platelets)
trial, which also investigated the use of a lower dose of platelets
for transfusion, although it involved a different patient
population ¡X patients with chemotherapy-induced thrombocytopenia,
the majority of whom had acute myeloid leukemia.

The STOP trial was stopped early because of safety concerns, in
particular 3 cases of grade 4 bleeding in the low-dose group,
which "may or may not be due to chance," said Ms. Heddle. However,
further analysis showed no benefit in the low-dose group, and a
trend toward a higher burden of bleeding, although this was not
statistically significant. She did acknowledge, however, that there
was a problem with the adjudication of grading of the bleeding
episodes, because there was some disagreement about the grades
assigned among those doing the assigning.

This issue did not arise in the PLADO trial, commented Dr. Slichter,
because the adjudication of bleeding grades was done by computer,
based on data gathered on a daily basis from physical examinations,
patient interviews, chart reviews, and laboratory results.

No Difference in Risk of Bleeding

The PLADO trial set out to determine the optimal prophylactic
platelet-dose strategy to prevent bleeding in thrombocytopenic
patients. It compared 3 different doses of platelets given by
transfusion: a low dose (1.1 ¡Ñ 1011 platelets/m2), a medium dose
(2.2 ¡Ñ 1011 platelets/m2), and a high dose (4.4 ¡Ñ 1011
platelets/m2). The medium dose corresponds most closely to the
standard dose currently used, Dr. Slichter noted.

Patients enrolled in the trial had hypoproliferative
thrombocytopenia and were expected to be hospitalized with platelet
counts of 10,000 mL or less for more than 5 days. This was the
trigger for a platelet transfusion, which was given prophylactically
on days when platelet counts reached or fell to below this level.

The results show that there was no significant difference in the
risk of bleeding across any of these doses, either in World Health
Organization grade 2 bleeding, which was the primary end point, or
in the more severe cases. "The incidence of grade 2 bleeding remains
high, at around 70%, regardless of dose," Dr. Slichter commented.

However, Dr. Kaushansky cautioned that "we must guard against
generalization," and emphasized that the recommendation pertains
only to patients comparable to those in the PLADO trial. Dr.
Slichter also made this point, and noted that nearly all the
participants had hematological malignancies (only 7 patients had
solid tumors), 70% had undergone bone-marrow transplants, and the
remaining 30% were treated with chemotherapy.

"This finding is important because it will decrease the utilization
of a scare resource and will also limit the exposure of patients to
blood products from donors," commented J. Evans Sadler, MD, PhD,
from the Division of Hematology at Washington University, in St.
Louis, Missouri. Dr. Sadler, who was not involved in the study, is a
cochair of the ASH Scientific Program Committee. He, too, predicted
that the results will change clinical practice.

Wait for Peer Review and Publication

"Not yet," urged Ron Strauss, MD, professor of pathology and
pediatrics at the University of Iowa Hospital, in Iowa City. "We
should continue to use the standard dose of platelets until these
results are peer reviewed and published," he commented to Medscape
Oncology, adding that conclusions are often tempered in the peer-
review process.

Dr. Strauss urged caution during an educational session. "I think it
is too risky to change practice," he said. However, Dr. Slichter
said that she disagreed, and that she felt the data were robust
enough to recommend a change in clinical practice. "It is safe based
on this study," she said.

"I am not sure," said Nancy Heddle, MSc, from McMaster University,
in Hamilton, Ontario. She also urged clinicians to wait until the
study undergoes peer review and publication before implementing
changes in clinical practice. At the same session, she presented
results from the STOP (Strategies for Transfusion of Platelets)
trial, which also investigated the use of a lower dose of platelets
for transfusion, although it involved a different patient
population ¡X patients with chemotherapy-induced thrombocytopenia,
the majority of whom had acute myeloid leukemia.

The STOP trial was stopped early because of safety concerns, in
particular 3 cases of grade 4 bleeding in the low-dose group,
which "may or may not be due to chance," said Ms. Heddle. However,
further analysis showed no benefit in the low-dose group, and a
trend toward a higher burden of bleeding, although this was not
statistically significant. She did acknowledge, however, that there
was a problem with the adjudication of grading of the bleeding
episodes, because there was some disagreement about the grades
assigned among those doing the assigning.

This issue did not arise in the PLADO trial, commented Dr. Slichter,
because the adjudication of bleeding grades was done by computer,
based on data gathered on a daily basis from physical examinations,
patient interviews, chart reviews, and laboratory results.

No Difference in Risk of Bleeding

The PLADO trial set out to determine the optimal prophylactic
platelet-dose strategy to prevent bleeding in thrombocytopenic
patients. It compared 3 different doses of platelets given by
transfusion: a low dose (1.1 ¡Ñ 1011 platelets/m2), a medium dose
(2.2 ¡Ñ 1011 platelets/m2), and a high dose (4.4 ¡Ñ 1011
platelets/m2). The medium dose corresponds most closely to the
standard dose currently used, Dr. Slichter noted.

Patients enrolled in the trial had hypoproliferative
thrombocytopenia and were expected to be hospitalized with platelet
counts of 10,000 mL or less for more than 5 days. This was the
trigger for a platelet transfusion, which was given prophylactically
on days when platelet counts reached or fell to below this level.

The results show that there was no significant difference in the
risk of bleeding across any of these doses, either in World Health
Organization grade 2 bleeding, which was the primary end point, or
in the more severe cases. "The incidence of grade 2 bleeding remains
high, at around 70%, regardless of dose," Dr. Slichter commented.

However, Dr. Kaushansky cautioned that "we must guard against
generalization," and emphasized that the recommendation pertains
only to patients comparable to those in the PLADO trial. Dr.
Slichter also made this point, and noted that nearly all the
participants had hematological malignancies (only 7 patients had
solid tumors), 70% had undergone bone-marrow transplants, and the
remaining 30% were treated with chemotherapy.

"This finding is important because it will decrease the utilization
of a scare resource and will also limit the exposure of patients to
blood products from donors," commented J. Evans Sadler, MD, PhD,
from the Division of Hematology at Washington University, in St.
Louis, Missouri. Dr. Sadler, who was not involved in the study, is a
cochair of the ASH Scientific Program Committee. He, too, predicted
that the results will change clinical practice.

Wait for Peer Review and Publication

"Not yet," urged Ron Strauss, MD, professor of pathology and
pediatrics at the University of Iowa Hospital, in Iowa City. "We
should continue to use the standard dose of platelets until these
results are peer reviewed and published," he commented to Medscape
Oncology, adding that conclusions are often tempered in the peer-
review process.

Dr. Strauss urged caution during an educational session. "I think it
is too risky to change practice," he said. However, Dr. Slichter
said that she disagreed, and that she felt the data were robust
enough to recommend a change in clinical practice. "It is safe based
on this study," she said.

"I am not sure," said Nancy Heddle, MSc, from McMaster University,
in Hamilton, Ontario. She also urged clinicians to wait until the
study undergoes peer review and publication before implementing
changes in clinical practice. At the same session, she presented
results from the STOP (Strategies for Transfusion of Platelets)
trial, which also investigated the use of a lower dose of platelets
for transfusion, although it involved a different patient
population ¡X patients with chemotherapy-induced thrombocytopenia,
the majority of whom had acute myeloid leukemia.

The STOP trial was stopped early because of safety concerns, in
particular 3 cases of grade 4 bleeding in the low-dose group,
which "may or may not be due to chance," said Ms. Heddle. However,
further analysis showed no benefit in the low-dose group, and a
trend toward a higher burden of bleeding, although this was not
statistically significant. She did acknowledge, however, that there
was a problem with the adjudication of grading of the bleeding
episodes, because there was some disagreement about the grades
assigned among those doing the assigning.

This issue did not arise in the PLADO trial, commented Dr. Slichter,
because the adjudication of bleeding grades was done by computer,
based on data gathered on a daily basis from physical examinations,
patient interviews, chart reviews, and laboratory results.

No Difference in Risk of Bleeding

The PLADO trial set out to determine the optimal prophylactic
platelet-dose strategy to prevent bleeding in thrombocytopenic
patients. It compared 3 different doses of platelets given by
transfusion: a low dose (1.1 ¡Ñ 1011 platelets/m2), a medium dose
(2.2 ¡Ñ 1011 platelets/m2), and a high dose (4.4 ¡Ñ 1011
platelets/m2). The medium dose corresponds most closely to the
standard dose currently used, Dr. Slichter noted.

Patients enrolled in the trial had hypoproliferative
thrombocytopenia and were expected to be hospitalized with platelet
counts of 10,000 mL or less for more than 5 days. This was the
trigger for a platelet transfusion, which was given prophylactically
on days when platelet counts reached or fell to below this level.

The results show that there was no significant difference in the
risk of bleeding across any of these doses, either in World Health
Organization grade 2 bleeding, which was the primary end point, or
in the more severe cases. "The incidence of grade 2 bleeding remains
high, at around 70%, regardless of dose," Dr. Slichter commented.

However, Dr. Kaushansky cautioned that "we must guard against
generalization," and emphasized that the recommendation pertains
only to patients comparable to those in the PLADO trial. Dr.
Slichter also made this point, and noted that nearly all the
participants had hematological malignancies (only 7 patients had
solid tumors), 70% had undergone bone-marrow transplants, and the
remaining 30% were treated with chemotherapy.

"This finding is important because it will decrease the utilization
of a scare resource and will also limit the exposure of patients to
blood products from donors," commented J. Evans Sadler, MD, PhD,
from the Division of Hematology at Washington University, in St.
Louis, Missouri. Dr. Sadler, who was not involved in the study, is a
cochair of the ASH Scientific Program Committee. He, too, predicted
that the results will change clinical practice.

Wait for Peer Review and Publication

"Not yet," urged Ron Strauss, MD, professor of pathology and
pediatrics at the University of Iowa Hospital, in Iowa City. "We
should continue to use the standard dose of platelets until these
results are peer reviewed and published," he commented to Medscape
Oncology, adding that conclusions are often tempered in the peer-
review process.

Dr. Strauss urged caution during an educational session. "I think it
is too risky to change practice," he said. However, Dr. Slichter
said that she disagreed, and that she felt the data were robust
enough to recommend a change in clinical practice. "It is safe based
on this study," she said.

"I am not sure," said Nancy Heddle, MSc, from McMaster University,
in Hamilton, Ontario. She also urged clinicians to wait until the
study undergoes peer review and publication before implementing
changes in clinical practice. At the same session, she presented
results from the STOP (Strategies for Transfusion of Platelets)
trial, which also investigated the use of a lower dose of platelets
for transfusion, although it involved a different patient
population ¡X patients with chemotherapy-induced thrombocytopenia,
the majority of whom had acute myeloid leukemia.

The STOP trial was stopped early because of safety concerns, in
particular 3 cases of grade 4 bleeding in the low-dose group,
which "may or may not be due to chance," said Ms. Heddle. However,
further analysis showed no benefit in the low-dose group, and a
trend toward a higher burden of bleeding, although this was not
statistically significant. She did acknowledge, however, that there
was a problem with the adjudication of grading of the bleeding
episodes, because there was some disagreement about the grades
assigned among those doing the assigning.

This issue did not arise in the PLADO trial, commented Dr. Slichter,
because the adjudication of bleeding grades was done by computer,
based on data gathered on a daily basis from physical examinations,
patient interviews, chart reviews, and laboratory results.

No Difference in Risk of Bleeding

The PLADO trial set out to determine the optimal prophylactic
platelet-dose strategy to prevent bleeding in thrombocytopenic
patients. It compared 3 different doses of platelets given by
transfusion: a low dose (1.1 ¡Ñ 1011 platelets/m2), a medium dose
(2.2 ¡Ñ 1011 platelets/m2), and a high dose (4.4 ¡Ñ 1011
platelets/m2). The medium dose corresponds most closely to the
standard dose currently used, Dr. Slichter noted.

Patients enrolled in the trial had hypoproliferative
thrombocytopenia and were expected to be hospitalized with platelet
counts of 10,000 mL or less for more than 5 days. This was the
trigger for a platelet transfusion, which was given prophylactically
on days when platelet counts reached or fell to below this level.

The results show that there was no significant difference in the
risk of bleeding across any of these doses, either in World Health
Organization grade 2 bleeding, which was the primary end point, or
in the more severe cases. "The incidence of grade 2 bleeding remains
high, at around 70%, regardless of dose," Dr. Slichter commented.

However, Dr. Kaushansky cautioned that "we must guard against
generalization," and emphasized that the recommendation pertains
only to patients comparable to those in the PLADO trial. Dr.
Slichter also made this point, and noted that nearly all the
participants had hematological malignancies (only 7 patients had
solid tumors), 70% had undergone bone-marrow transplants, and the
remaining 30% were treated with chemotherapy.

"This finding is important because it will decrease the utilization
of a scare resource and will also limit the exposure of patients to
blood products from donors," commented J. Evans Sadler, MD, PhD,
from the Division of Hematology at Washington University, in St.
Louis, Missouri. Dr. Sadler, who was not involved in the study, is a
cochair of the ASH Scientific Program Committee. He, too, predicted
that the results will change clinical practice.

Wait for Peer Review and Publication

"Not yet," urged Ron Strauss, MD, professor of pathology and
pediatrics at the University of Iowa Hospital, in Iowa City. "We
should continue to use the standard dose of platelets until these
results are peer reviewed and published," he commented to Medscape
Oncology, adding that conclusions are often tempered in the peer-
review process.

Dr. Strauss urged caution during an educational session. "I think it
is too risky to change practice," he said. However, Dr. Slichter
said that she disagreed, and that she felt the data were robust
enough to recommend a change in clinical practice. "It is safe based
on this study," she said.

"I am not sure," said Nancy Heddle, MSc, from McMaster University,
in Hamilton, Ontario. She also urged clinicians to wait until the
study undergoes peer review and publication before implementing
changes in clinical practice. At the same session, she presented
results from the STOP (Strategies for Transfusion of Platelets)
trial, which also investigated the use of a lower dose of platelets
for transfusion, although it involved a different patient
population ¡X patients with chemotherapy-induced thrombocytopenia,
the majority of whom had acute myeloid leukemia.

The STOP trial was stopped early because of safety concerns, in
particular 3 cases of grade 4 bleeding in the low-dose group,
which "may or may not be due to chance," said Ms. Heddle. However,
further analysis showed no benefit in the low-dose group, and a
trend toward a higher burden of bleeding, although this was not
statistically significant. She did acknowledge, however, that there
was a problem with the adjudication of grading of the bleeding
episodes, because there was some disagreement about the grades
assigned among those doing the assigning.

This issue did not arise in the PLADO trial, commented Dr. Slichter,
because the adjudication of bleeding grades was done by computer,
based on data gathered on a daily basis from physical examinations,
patient interviews, chart reviews, and laboratory results.

No Difference in Risk of Bleeding

The PLADO trial set out to determine the optimal prophylactic
platelet-dose strategy to prevent bleeding in thrombocytopenic
patients. It compared 3 different doses of platelets given by
transfusion: a low dose (1.1 ¡Ñ 1011 platelets/m2), a medium dose
(2.2 ¡Ñ 1011 platelets/m2), and a high dose (4.4 ¡Ñ 1011
platelets/m2). The medium dose corresponds most closely to the
standard dose currently used, Dr. Slichter noted.

Patients enrolled in the trial had hypoproliferative
thrombocytopenia and were expected to be hospitalized with platelet
counts of 10,000 mL or less for more than 5 days. This was the
trigger for a platelet transfusion, which was given prophylactically
on days when platelet counts reached or fell to below this level.

The results show that there was no significant difference in the
risk of bleeding across any of these doses, either in World Health
Organization grade 2 bleeding, which was the primary end point, or
in the more severe cases. "The incidence of grade 2 bleeding remains
high, at around 70%, regardless of dose," Dr. Slichter commented.

In the first study to ever assess the prognostic value of a change
in heart rate (HR) over a number of years, French doctors have found
that there is a relation between this variable and mortality. Dr
Xavier Jouven (Hôpital Européen Georges Pompidou, Paris, France) and
colleagues report their findings in a study published online
November 7, 2008 in the American Journal of Cardiology [1].

They found that in a cohort of healthy policemen, HR at rest and its
change over 5 years were both predictors of death, independent of
the standard cardiovascular risk factors. Those whose HR rose by
more than 3 beats per minute (bpm) over this time period had an
almost 20% increased mortality risk compared with men whose HR
remained unchanged.

Jouven told heartwire that this is "an important paper and the
second step" in a jigsaw. "We knew before that if a person has a
high heart rate, they have a high mortality. Now this article shows
we are advancing in the research concerning the potential
association between HR and mortality."

Dr Franz Messerli (St Luke's-Roosevelt Hospital, New York) commented
to heartwire: "The present study is unique in that it shows that
patients whose heart rate increased during a 5-year period had
an . . . increased mortality risk. Of note, the policemen who did
best were the ones who had a low heart rate at the beginning of the
PARIS prospective study and whose heart rate remained unchanged."

Reduced HR Associated With 14% Lower Risk of Death

The observational, although prospective, study followed 5139
asymptomatic men (aged 42 to 53 years) who were recruited from 1967
to 1972 and had their HRs measured at rest in standardized
conditions every year for 5 consecutive years. HR change was defined
as the difference between HR at examination 5 and HR at inclusion.
Subjects were divided into the following tertiles: decrease >4 bpm;
unchanged (from -4 to +3 bpm); or increase >3 bpm.

After adjustments were made for confounding factors, including
baseline HR at rest, and compared with subjects with unchanged HRs,
those with decreased HRs during the 5 years had a 14% decreased
mortality risk (RR, 0.86; 95% CI, 0.74 to 1.00; p=0.05), whereas men
with increased HRs during the 5 years had a 19% increased mortality
risk (RR, 1.19; 95% CI, 1.04 to 1.37; p<0.012).

Because the study was performed in relatively young French
policemen, the generalizability of the findings to women or a more
unselected or recent population cohort is unclear, the researchers
point out.

They say that the association between high HR at rest and mortality
is consistent with data already published in a number of
epidemiologic studies, and that high HR at rest could reflect
underlying abnormalities, possibly via increased mechanical stress
on the arterial wall and heart.

"We found that change in HR over a 5-year period conferred
additional information beyond HR at rest and the usual risk factors,
[and] was an independent predictor of mortality in middle-aged men,"
they observe.

Exercise Keeps Heart Rate Low

Messerli told heartwire that "the most common reason for a slow
heart rate in young to middle-aged subjects, such as in the present
study, is regular conditioning. Conceivably therefore, subjects in
this group were the ones who exercised regularly and continued to
exercise regularly throughout the 5-year period, thereby keeping
heart rate slow. As expected, BMI was lowest in this group."

"It is of little surprise, then, that these slow heart rate
policemen had a drastically lower mortality than those who started
out with an increased heart rate [that] accelerated . . . even more
during the 5-year period," he added.

Jouven told heartwire that the next step to prove an association
will be with some kind of interventional trial aimed at
investigating whether an induced HR decrease--with, for example
regular exercise--is associated with a decrease in mortality
risk. "If we change HR, do we change mortality?" he wondered.


Jouven X, Empana JP, Escolano S et al. Relation of heart rate at
rest and long-term (>20 years) death rate in initially healthy
middle-aged men. Am J Cardiol. Published online before print
November 7, 2008. DOI:10.1016/j.amjcard.2008.08.071.

In the largest study to date looking at the issue, researchers
report that survival in heart-transplant recipients is significantly
reduced if recipients receive a heart from a donor of the opposite
sex.

According to Dr Eric Weiss (Johns Hopkins Medical Institutions,
Baltimore, MD), who presented the analysis during the American Heart
Association 2008 Scientific Sessions, the findings should help
transplant programs choose the best recipient for a heart transplant
when a donor organ becomes available.

In an interview with heartwire, Weiss explained that gender matching
has been explored in other solid-organ transplants and even in the
setting of heart transplantation, but in small numbers, typically at
single-center institutions. For his study, Weiss and colleagues used
the United Network for Organ Sharing, containing information on more
than 18 000 heart-transplant recipients who underwent
transplantation between 1998 and 2007.

They found that 77% of men and 51% of women had actually been
matched by gender to their donor and that gender-matching was
associated with a 15% reduction in adjusted, all-cause, cumulative
mortality. Patients at greatest risk of dying over the study follow-
up were women who had received hearts from male donors, a
statistically significant 23% increased risk as compared with men
who received hearts from male donors, followed by males who received
hearts from female donors, a 15% increased risk. By far, male
recipients of male hearts had the lowest mortality out to nine years-
-61%, as compared with 54% in women who'd received a heart from a
male donor, a statistically significant difference (p<0.001 by log
rank test).

In secondary analyses, the authors also looked at gender mismatch
and transplant rejection and found that gender mismatch was
associated with organ rejection only in men who'd received hearts
from female donors. In fact, female recipient gender in itself was a
risk factor for rejection, regardless of the sex of the donor.

According to Weiss, gender is already taken into account during
donor-recipient selection, in part due to the size of the chest
cavity. Many women, for example, cannot physically accommodate a
larger (male) heart due to the constraints placed by the chest wall.
Physiologically, he added, sex matters in terms of functional
capacity. "The heart needs to have the functional reserve, the
beating power, to pump to a large body," Weiss explained.

Other factors include the minor histocompatibility antigen on the Y
chromosome, believed to be an important cause of transplant
rejection, and what Weiss called the "hormonal milieu," which
appears to confer benefit when the donor and recipient are of the
same gender. But overall, he said, the reasons underpinning gender-
matching are incompletely understood and were not something that
could be probed in any depth in the current study.

"With these multi-institutional databases, it's a little hard,
because we are at the mercy of the variables that individual
institutions have collected," Weiss said. "So this study would have
been designed a bit differently if we had been collecting the
variables ourselves."

According to Weiss, the current study is part of an ongoing effort
to create a risk score for predicting patient outcomes. "Our focus
is on understanding factors that lead to improved outcomes after
heart transplantation. This is one factor, and clearly there are
other factors--as we learn more about this we can improve our
ability to match donors and recipients."

He emphasized that patients who have received a heart from someone
of the opposite sex or physicians with patients whose hearts
are "gender mismatched" should not be overly concerned. "We don't
want people to think that this somehow means they're going to have a
poor outcome. It still is much better to receive a transplant than
to live with end-stage heart failure, even if you have a mismatched
organ, especially if the organ is matched in a lot of other ways,
from a [human leukocyte antigen] standpoint or an age standpoint--
that kind of thing."

But he also emphasized that the information could help guide
decision-making, particularly since the number of patients needing
heart transplantation far exceeds the number of donor organs. "If
all else is equal and you're trying to decide which recipient should
get a heart, it would probably be better to take a donor of the same
sex," he said.

Custom-compounded plant-derived hormone cream may not only improve
menopausal symptoms, including depression, anxiety, and pain, it may
also provide an anti-inflammatory effect without increasing blood-
clot formation, a small study suggests.

Researchers at the University of Texas Health Science Center, in
Tyler, found promising 1-year safety and efficacy results in 75 peri-
  and postmenopausal women who received individually formulated
hormone-replacement therapy applied as a cream to the skin.

"The 1-year findings are pretty encouraging," lead author Kenna
Stephenson, MD, told Medscape Psychiatry. "We thought compounded
transdermal hormones would relieve menopausal symptoms, but we
didn't anticipate that they would also have a favorable effect on
inflammatory, hemostatic, and cardiometabolic pathways."

The study was presented here at the American Heart Association 2008
Scientific Sessions.

Unproven Safety and Efficacy

In the United States, about 15 million women are currently peri- or
postmenopausal and, as such, have an increased risk for
cardiovascular disease, said Dr. Stephenson.

Since the Women's Health Initiative study showed an increased risk
for breast cancer, stroke, and dementia with conventional hormone
therapy, more women have been seeking alternative treatments for
menopausal symptoms, such as hot flashes, night sweats, disrupted
sleep, and irritability.

"We've seen an increase in the use of compounded transdermal hormone
therapies among this population, but the safety and efficacy of
these formulations have not been studied," she said.

To evaluate the hemostatic and anti-inflammatory effects of a
compounded transdermal hormone-replacement therapy, the researchers
recruited 150 peri- and postmenopausal women, aged 30 to 70 years.

Half were assigned to usual care and the rest were assigned to the
compounded cream. Usual care was defined as conventional hormone
therapy of conjugated equine estrogens and medroxyprogesterone.

The transdermal hormonal therapy consisted of plant-derived
estrogen, progesterone, and sometimes testosterone and
dehydroepiandrostenedione (DHEA).

Subjects in the transdermal-cream group were prescribed
individualized therapy on the basis of their hormone levels. The
women applied the cream to the skin once or twice daily to receive
the target dose.

Although progesterone and DHEA are available over the counter in the
United States, the doses of prescribed therapy, such as those used
in the study, are much higher.

Encouraging Findings

At 12 months, the subjects who received the study treatment had:

Significant decreases in depression and anxiety, as assessed by the
Hamilton Depression Scale and the Hamilton Anxiety Scale
Significant improvements in quality of life and menopausal symptoms,
such as hot flashes and night sweats, as assessed by the Greene
Climacteric Scale
No harmful hemostatic effects, as indicated by significant decreases
in fibrinogen and factor VII, and no significant changes in factor
VIII or plasminogen activator inhibitor type I.
No harmful anti-inflammatory effects, as shown by significant
decreases in C-reactive protein (CRP), and no significant changes in
interleukin-6
Beneficial cardiometabolic effects, as shown by significant
decreases in systolic blood pressure, pulse pressure, fasting
glucose, and fasting triglycerides.

Still Early Days

"All hormones are not equal, and all hormone preparations are not
equal," said Dr. Stephenson. "There are distinctly different risks
and effects on inflammatory and thrombotic factors and
cardiovascular biomarkers."

In this study, CRP and triglycerides decreased in women who received
transdermal plant-derived compound hormones, whereas other studies
have shown increased CRP and triglycerides in women receiving
conventional equine and synthetic hormone therapy, she added.

However, "larger clinical trials are needed to determine whether
this therapy is a good alternative to conventional hormone-
replacement therapy," she said.

"Patients Like It"

"Many perimenopausal and postmenopausal women with mood symptoms may
be given antidepressant therapy or anti-anxiety therapy, but by
treating the underlying cause ¡X hormonal changes ¡X we see a
statistically significant improvement in dysphoria," said Dr.
Stephenson.

She added that patients in her clinical practice who receive
compounded transdermal hormone-replacement therapy like it because
it is easy, there are few adverse effects, it is very well
tolerated, and it is effective for mood symptoms and hormone-related
symptoms, such as vaginal dryness and night sweats."

It is important, she added, that a trained compounding pharmacist
prepare transdermal hormone-replacement therapy. The International
Academy of Compounding Pharmacists, which helped fund the study,
lists such pharmacists on their Web site. Other information is
available from the Professional Compounding Centers of America
(PCCA) and the PCCA Canada Web sites.

The study was partly funded by the Progesterone Foundation and the
International Academy of Compounding Pharmacists. The study authors
have disclosed no relevant financial relationships.

American Heart Association (AHA) 2008 Scientific Sessions: Abstract
5071. Presented November 11, 2008.

Patients with atrial fibrillation (AF) who received dronedarone
(Multaq, Sanofi-Aventis) were less often hospitalized for
cardiovascular reasons regardless of whether the cause of hospital
admission was AF or something else, in a large placebo-controlled
trial that--researchers say--offered those hints and others that
some of the drug's clinical benefits may derive from
nonantiarrhythmic effects [1].

Moreover, as an antiarrhythmic agent, dronedarone displayed both
rate- and rhythm-controlling properties in the trial, called ATHENA,
which randomized >4500 "moderate- to high-risk" patients with AF
[2].

Those secondary findings were reported here last week at the
American Heart Association 2008 Scientific Sessions. In
presentations earlier this year, as reported by heartwire, the trial
had shown a 24% drop in the primary end point of CV hospitalization
or death and a 34% decline in risk of stroke in the dronedarone
group compared with placebo over its mean 21-month follow-up.

"The amazing thing about this data set is the consistency of the
findings," Dr Richard L Page (University of Washington, Seattle),
told heartwire, pointing to independent dronedarone-related declines
in hospitalization rate of 37% when the cause of admission was AF
and 14% when it wasn't AF (both significant), 30% when it was acute
coronary syndromes (perhaps significant), and 14% (nonsignificant)
when the cause was heart failure. The "intriguing but not
definitive" risk decreases that fell short of significance, he
said, "at least all go in the right direction."

The results of ATHENA can be interpreted only so far, as the drug
has not been directly compared with the likeliest drug AF patients
might now receive, amiodarone; a comparator trial called DIONYSUS is
ongoing, observed Page, who reported ATHENA's secondary results at
the meeting. But if the drug's benefits vs placebo seen in ATHENA
are borne out in further studies, he noted, some AF patients who
might not respond to or tolerate amiodarone could become candidates
for dronedarone.

Observers of ATHENA agree that dronedarone has so far shown a fairly
benign safety profile, with rates of clinically important adverse
events similar to those seen with placebo. That contrasts it with
its chemical cousin amiodarone, which is notorious for its potential
end-organ toxicities.

But observers also note that dronedarone's ability to suppress AF
doesn't seem quite as strong as that of amiodarone. Moreover, many
have reservations about using the drug in patients with heart
failure; the two conditions commonly coexist. As previously reported
by heartwire, a trial called ANDROMEDA had been terminated early
after an apparent mortality increase with the drug among the
trial's "high-risk" patients with systolic heart failure. ATHENA
excluded patients with NYHA class 4 heart failure.

The trial randomized patients with paroxysmal or persistent AF or
atrial flutter to receive dronedarone (400 mg twice daily, n=2301)
or placebo (n=2327); beta blockers, calcium-channel blockers, and
digoxin were used as frequently in one group as the other.
Participants were required to be older than 75 years or, in the
presence of at least one other risk factor, older than 70 years; the
other risk factors could be diabetes, hypertension, a history of
stroke, reduced LVEF, or atrial enlargement.

There was no significant difference in rate of non-CV
hospitalizations.

Among patients in sinus rhythm at baseline, the median time to first
recurrence of AF or atrial flutter was significantly improved in the
active-therapy group: 737 days vs 498 days on placebo (hazard ratio
0.75, 95% CI 0.68¡V0.82; p<0.001).

At least one electrical cardioversion occurred in 14.7% and 20.7% of
the patients, respectively (HR 0.68, 95% CI 0.60¡V0.79; p<0.001).

Associated with the significant observed dronedarone-related
reductions in morbidity was significantly reduced hospitalization
time for patients taking the drug, observed Page. Actively treated
patients spent about 28% fewer days in the hospital and about 35%
fewer when hospitalized for CV reasons (both differences p<0.001).

"That reduction of almost 4000 hospital days translates to a
decrease of 1.26 hospitalization days per patient per year,"
according to Page. "Almost 500 of those days were in the CCU or ICU,
and a good number were in medium care." That, he said, "would
translate into significant savings."

Interestingly, heart rate during AF or atrial flutter also decreased
significantly in the dronedarone group compared with placebo; the
median and mean both fell by 9 bpm (p<0.001 for both). That and
other observations, according to Page, suggest that dronedarone,
like amiodarone, has cardiovascular effects that aren't directly
antiarrhythmic but may contribute to clinical benefits.

For example, Page observed that systolic blood pressure dropped
among ATHENA's actively treated patients compared with controls. "A
little bit, by about 2 mm Hg, which may play a role when it's spread
over this many patients." Also, as heartwire previously reported,
dronedarone appeared to reduce the risk of stroke.

Moreover, according to Page, there were 473 patients in the trial,
178 on dronedarone and 295 in the placebo group (p<0.001), who never
produced an ECG showing sinus rhythm and so were classified as
having permanent AF--yet as a group showed a trend of a 26% drop in
risk of CV hospitalization or death (p<0.10). "They had a hazard
ratio [for the primary end point] almost identical to the overall
study population," he said. "They did not reach a 0.05 p value
because they were in the minority, but it suggests that there could
be something going on here over and above the antiarrhythmic effect."

ATHENA was sponsored by Sanofi-Aventis. Page has disclosed being an
advisor or consultant for Sanofi-Aventis and Astellas. At least two
ATHENA coauthors are employees of Sanofi-Aventis.


Torp-Pedersen C, Page RL, Connolly SJ, et al. The effect of
dronedarone on hospitalizations in patients with atrial
fibrillation. Results from the ATHENA study. American Heart
Association 2008 Scientific Sessions; November 8-12, 2008; New
Orleans, LA. Abstract 4101.
Page RL, Connolly SJ; Crijns HJ, et al. Rhythm- and rate-controlling
effects of dronedarone in patients with atrial fibrillation:
Insights from the ATHENA trial. American Heart Association 2008
Scientific Sessions; November 8-12, 2008; New Orleans, LA. Abstract
4097.

An international genomewide association study has identified 6
genetic loci associated with serum lipid levels in European
populations. This brings to 22 the total number of genomic regions
affecting serum lipid levels, a major risk factor in cardiovascular
disease. The study, presented here at the American Society of Human
Genetics 58th Annual Meeting, is part of the ENGAGE Consortium, an
extensive research project funded by the European Union.

Presenter Samuli Ripatti, PhD, from the Karolinska Institute, Solna,
Stockholm, Sweden, and the University of Helsinki, Finland, reported
that the study combined genomewide association data from 16 European
cohorts of nonselected population-based samples. A total of 22,562
samples were collected. "We also extended the definition of Europe a
bit to be inclusive," he added, noting that there were 424 samples
from Australia.

The threshold for genomewide significance was <5 x 10¡V8. Analysis
for loci associated with total cholesterol levels found 3 loci not
previously identified in genomewide association studies: TMEM57 (P =
5.4 x 10¡V10), ABCG5 (P = 1.5 x 10¡V11), and FADS3/FADS2 (P = 1.5 x
10-10), on chromosomes 1, 2, and 11 respectively. An additional
locus on chromosome 7 was associated with low-density lipoprotein
(LDL) cholesterol levels (DNAH11; P = 6.1 x 10¡V9), and 2 additional
loci were associated with serum high-density lipoprotein (HDL)
cholesterol levels: the CTCF-PRMT8 region (P = 8.3 x 10¡V16) on
chromosome 16 and the MADD-FOLH1 region (P = 6 x 10¡V11) on
chromosome 11. The large HDL-related region on chromosome 11 merits
further functional studies.

The 22 genomic regions associated with serum lipid levels account
for as much as 5.6% of the variation in serum lipid levels at the
population level. Three of these loci have differential effects in
men and women. "The females, in total, have more than 2 times the
effect size than the males," said Dr. Ripatti in his presentation.

Senior author Cornelia M. van Duijn, PhD, head of the Genetic
Epidemiology Unit, Erasmus University Medical Center, Rotterdam, the
Netherlands, commented to Medscape Pathology & Lab Medicine by
email: "Although we know a lot about the difference in the blood
distribution of lipids between men and women, in particular
concerning HDL and triglycerides, we know very little about
differences in the impact of genes in humans. The reason is
statistical," said Dr. van Duijn.

"To show differences between subgroups (in this case, men vs women),
we needed roughly 4 times the sample size than that needed to
discover the gene.... With 20,000 to 30,000, we are beginning to
find genes with small effects. We need to study more than 100,000
persons to find genes that act only in men or women," Dr. van Duijn
observed. "We are trying to achieve this number by merging consortia
into a large one: global lipids."

To calculate genetic-risk scores, the investigators not only looked
at the risk alleles per person, but also weighted risk alleles by
their effect sizes, as estimated in the complement cohorts. They
calculated genetic risk for subjects in the Rotterdam study, a large
longitudinal study, focused on subjects older than 55 years.

Dr. van Duijn added: "If you are interested in the effect of lipids
[over a] lifetime, you do not want to study a young population, in
which there will be many persons who still have not developed
pathology yet, but who will in the future.... In women in
particular, the lipid levels change drastically after menopause (¡Ó50
years). This is one of the 'forgotten' side effects. We tend to
think of osteoporosis as the major problem, but lipids change as
dramatically postmenopausally. In the Rotterdam study, we can be
fairly sure that we can see the lipid problems."

The investigators looked at the predictive power of the genetic-risk
scores for future cases of hypercholesterolemia, intima-media
thickness, and coronary heart disease. "The bottom line," said Dr.
Ripatti, "was when we looked separately at the risk scores based on
the HDL genes, the LDL genes, and the total-cholesterol genes. One
of the findings was that the total-cholesterol genes had the most
predictive power for all of these." Total-cholesterol scores were
significantly associated with risk for hypercholesterolemia (P
< .001), intima-media thickness (P = .001), and coronary heart
disease (P = .042).

Medscape Pathology & Lab Medicine also spoke with comoderator Ruth
McPherson, MD, PhD, FRCPC, director of the Lipid Clinic, Lipid
Research Laboratory, University of Ottawa Heart Institute, in
Ontario. "We're now having the opportunity to go beyond SNPs [single-
nucleotide polymorphisms] that confer effects on [coronary heart
disease] risk factors, like proteins that are associated with risk,
to actually look at SNPs that may have gender-specificity," Dr.
McPherson said.

"We've known in genetics for many years, in many areas, that genetic
variants may interact with other factors...so that should be pointed
out as something that we have to do in the consortiums that are
sharing their data from various genomewide association studies,"
said Dr. McPherson. "We're now able to look at things like gender
effects and effects of other lifestyle factors, looking at gene-
environment interactions. And I think that's going to be pretty
exciting."