The US Food and Drug Administration (FDA) has granted orphan drug
designation for ganciclovir ophthalmic gel in the treatment of acute
herpetic keratitis and tissue repair cells in the treatment of
dilated cardiomyopathy.


Orphan Drug Ganciclovir for Treatment of Acute Herpetic Keratitis

On April 16, the FDA granted orphan drug designation to ganciclovir
ophthalmic gel (Sirion Therapeutics, Inc) for the treatment of acute
herpetic keratitis, a herpes simplex virus that is reported to affect
approximately 50,000 people annually in the United States.

With orphan drug designation, ganciclovir is the first topical
ophthalmic antiviral treatment launched in more than 2 decades. The
drug inhibits viral DNA synthesis as a result of phosphorylation to a
substrate that competitively inhibits the binding of deoxyguanosine
triphosphate to DNA polymerase. Sirion claims that the safety profile
of ganciclovir is superior to that of trifluridine, the most common
topical ophthalmic antiviral currently prescribed for herpes simplex
keratitis.

Sirion obtained rights to the drug in January from Laboratoires Thea,
which markets the drug in Europe under the brand name Virgan. Under
the agreement, Sirion will be allowed to market the drug in the
United States using the Virgan trade name.


Orphan Drug Tissue Repair Cells for Treatment of Dilated
Cardiomyopathy

On February 1, the FDA granted orphan drug designation for tissue
repair cells (TRCs; Aastrom Biosciences, Inc) for use in the
treatment of dilated cardiomyopathy, a group of disorders in which
the ventricles enlarge but are not able to pump an adequate supply of
blood, resulting in heart failure.

Dilated cardiomyopathy affects an estimated 120,000 to 150,000 people
in the United States and is characterized by a high mortality rate.
To date, the only effective long-term treatment for patients with end-
stage disease is heart transplantation.

Research suggests that high doses of stem cells and progenitor cells
may slow or reverse disease progression in the hearts of patients
with dilated cardiomyopathy. TRCs, which contain a large number of
stem cells and progenitor cells derived from a small sample of the
patient's bone marrow, are intended to induce heart tissue
regeneration and may delay or eliminate the need for heart
transplantation.

Publication of cardiac-surgery mortality data in the UK appears to
have been associated with better survival rates, without a reduction
in high-risk procedures, a new study suggests [1].

The retrospective analysis, published online in Heart, examined
predicted and risk-adjusted mortality in almost 25 730 patients who
had a first coronary artery bypass surgery over an eight-year period
spanning the time when cardiac-surgery mortality data was introduced,
in 2001. The surgeries were performed by 30 surgeons in four major
National Health Service (NHS) sites.

Results showed that the death rate for CABG patients after public
disclosure was significantly lower than it had been before. The
actual death rate fell from 2.4% of all CABG patients in the period
1997¡V1998 to 1.8% in 2004¡V2005. In contrast, the predicted death
rate steadily rose from 3% to 3.5%, suggesting that more high-risk
patients were being taken on. The proportions of elderly patients
aged over 80 and those with kidney disease, a recent MI, or
peripheral vascular disease all significantly increased.

The authors, led by Dr Ben Bridgewater (South Manchester University
Hospital, Manchester, UK), note that supporters of public disclosure
of surgical results argue that it will help drive improvements in
quality, but opponents believe that it promotes risk-averse behavior
by discouraging surgeons from accepting high-risk patients who would
otherwise benefit from surgery. The opponents¡¦ view is supported by
several surveys in US states with public disclosure of results; for
example, in Pennsylvania, more than half of the cardiologists
surveyed thought they had more difficulty in finding surgeons willing
to perform CABG on high-risk patients, and in New York, two thirds of
surgeons said they had refused to treat at least one patient with
high-risk CABG in the previous year, primarily because of public
reporting.

But this UK study found no evidence to suggest that public disclosure
of outcomes has led to a significant number of patients at high risk
being denied operations. ¡§If publication of surgical mortality data
had driven surgeons to turn down significant numbers of high-risk
patients, we would expect to see that reflected in a decrease in the
number of high-risk cases coming to surgery. This study suggests that
the effect may not be as large as is feared,¡¨ Bridgewater et al
write.

They say that it would be informative to study all patients referred
to surgery, rather than just those undergoing a procedure, to
determine whether public accountability has led to an increase in
surgical ¡¥¡¥turndowns¡¦¡¦ and to also study patients undergoing PCI
to compare trends in surgery (where UK results are currently
subjected to public scrutiny) and PCI (where they are not).

Bridgewater B, Grayson AD, Brooks N, et al. Has the publication of
cardiac surgery outcome data been associated with changes in practice
in northwest England: An analysis of 25 730 patients undergoing CABG
surgery under 30 surgeons over eight years. Heart 2007;
DOI:10.1136/hrt.2006.106393. Available at: http://heart.bmj.com.

Increased levels of two commonly measured biomarkers, taken
together, are significantly predictive of both all-cause mortality
and cardiac allograft vasculopathy (CAV) in patients with
transplanted hearts and could help distinguish those who might need
further, perhaps more invasive, testing from those who probably
don't, say researchers here at the International Society for Heart
and Lung Transplantation (ISHLT) 2007 Annual Meeting [1].

Both measures--C-reactive protein (CRP) and N-terminal pro-brain-
type natriuretic peptide (NT-proBNP)--were predictive of mortality
individually, but neither, on their own, was independently related
to a presence of CAV, according an analysis reported by Dr Satish
Arora (Rikshospitalet-Radiumhospitalet Medical Center, Oslo,
Norway). It was the combination of the two tests that was
prognostically most helpful, he told heartwire.

According to this first study to explore the paired biomarkers in
cardiac-transplant patients, Arora said, the positive predictive
value of two "positive" tests for CAV was about 16%, while their
sensitivity and specificity were about 70% and 60%, respectively. In
practical terms, he said, that makes them "more of a rule-out test
than a rule-in test," as normal levels of both would provide some
confidence that a more invasive evaluation, such as intravascular
ultrasound, may not be necessary.

The median levels of NT-proBNP and CRP measured at an annual
evaluation of 210 transplanted patients were 45.6 pmol/L and 1.41
mg/L, respectively; CAV was identified in 37% of the group over a
median follow-up of 2.2 years, and 19% died over a median
observation of 5.4 years.

Although increased natriuretic peptide levels in patients with
native heart disease are widely considered a response to ventricular
stretch, that may not explain their physiologic importance in
transplanted patients, Arora told heartwire. In their cohort, he
said, high NT-proBNP levels were not consistently associated with
poor allograft function as measured by echocardiography, suggesting
that natriuretic peptide elevations in transplanted patients may
derive from a process other than myocardial stretch--perhaps
directly from CAV.

Other evidence that the natriuretic peptides may provide information
in transplanted heart disease different from that in native heart
disease emerged in a study presented at the ISHLT sessions by Dr
Vijay S Vaidya (University of California, Los Angeles) [2].

In 130 consecutive heart-transplant patients who had brain-type
natriuretic peptide (BNP) levels measured at the time of right-heart
catheterization, levels >150 pg/mL were found to have a sensitivity
of only 45%, a specificity of 65%, a positive predictive value of
3.7%, and a negative predictive value of 2.4% for the detection of
heart failure--defined as the characteristic symptoms plus a
pulmonary capillary wedge pressure >15 mm Hg.

In patients with transplanted hearts, therefore, increased levels of
BNP do not appear to be a reliable indicator of clinically relevant
heart failure, as they are in nontransplanted patients, Vaidya said.
The reason for the difference is unclear, but, he speculated, it may
be that the denervation of transplanted hearts alters natriuretic
peptide responses.

Arora S, Gullestad L, Wergeland R, et al. Combined analysis of NT-
proBNP and C-reactive protein improves their predictive value for
development of cardiac allograft vasculopathy and all-cause
mortality but not acute cellular rejection in heart transplant
recipients. International Society for Heart and Lung Transplantation
2007 Annual Meeting; April 26, 2007; San Francisco, CA. Abstract
168.
Vaidya VS, Yajnik M, Patel JK, et al. The validity of BNP blood
levels to detect heart failure in heart transplant patients.
International Society for Heart and Lung Transplantation 2007 Annual
Meeting; April 26, 2007; San Francisco, CA. Abstract 169.

In a cohort of Japanese patients with optimized medical therapy and
controlled hypertension, the addition of the angiotensin-receptor
blocker (ARB) valsartan (Diovan, Novartis) provided additional
cardiovascular benefit when compared with optimal therapy alone [1].
Adding valsartan on top of calcium-channel blockers, ACE inhibitors,
and beta blockers further reduced the risk of stroke, angina
pectoris, and heart failure, a benefit that cannot be entirely
explained by a difference in blood-pressure control, say
investigators.

These are the results of the Jikei Heart Study, first presented at
the World Congress of Cardiology (WCC) 2006 and reported by
heartwire at that time. Dr Björn Dahlöf (Göteborg University,
Sweden), who presented the findings during the late-breaking
clinical-trials session in Barcelona, Spain, previously commented
that the Jikei Heart Study is the first to show a clinical benefit
of adding valsartan for blood-pressure control in an Asian
population, specifically the Japanese population.

"This is highly relevant for clinical practice," Dahlöf told
heartwire at the time of presentation. "I think we have to consider
even more aggressive blood-pressure control, and not only that, but
what kind of agent we use to achieve that control."

Two hypertension experts, however, challenge the conclusions reached
by the Jikei Heart investigators, stating that "one should not
accept at face value the main conclusions" of the study [2]. In an
editorial by Drs Jan Staessen and Tom Richart (University of Leuven,
Belgium), the pair contends that the study does not prove that
valsartan, or any other ARB for that matter, confers a benefit
beyond blood-pressure lowering.

Moreover, the editorialists argue there are numerous inherent study
weaknesses, including "compromises" investigators made to make the
trial feasible. For example, the sample size and incidence of hard
clinical events were lower than in other trials, and the addition of
non-ARB therapy in the comparator arm did not "catch up" with the
addition of valsartan until the second year of follow-up. In
addition, the study design--Jikei Heart was an open-label end-point
trial--could have introduced bias into the study, even though end
points were adjudicated.

The Jikei Heart Study, with lead investigator Dr Seibu Mochizuki
(The Jikei University School of Medicine), as well as the editorial
by Staessen and Richart, is now published in the April 28, 2007
issue of the Lancet.

PROBE design

In the Jikei Heart Study, investigators randomized 3081 Japanese
patients with hypertension, coronary heart disease, and/or heart
failure to conventional therapy or to conventional therapy plus
valsartan. The aim of the prospective, randomized, open-label,
blinded-end-point (PROBE) study was to reduce blood-pressure levels
to 130/80 mm Hg, the hypothesis being that the addition of the ARB
would further improve outcomes. The primary end point was a
composite of cardiovascular morbidity and mortality.

Patients were well matched in both treatment arms, and blood
pressure was well treated from the beginning, with an average
baseline blood pressure of 139/81 mm Hg. At baseline, more than 75%
of patients were treated with a calcium-channel blocker, more than
40% with an ACE inhibitor, approximately 20% with a beta blocker,
and 7% were taking diuretics. In the valsartan-treatment arm, the
recommended dose was 40 to 160 mg/day, with 76 mg the average dose
prescribed.


Overall, there was no significant difference in blood-pressure
reduction or heart rate between the valsartan-treated patients and
patients treated without the ARB. The trial, however, was halted
early, with a significant cardiovascular benefit observed among
those treated with valsartan. The 39% reduction in the primary end
point was mainly attributable to fewer incidences of stroke and
transient ischemic attacks, angina, and heart failure. There was no
mortality benefit, including cardiovascular mortality, nor was there
a reduction in the risk of MI.

Significant differences in early blood-pressure lowering

In their editorial, Staessen and Richart point out that while there
were no significant differences in blood pressure at study
completion, the two treatment strategies did yield early differences
in systolic and diastolic blood pressure, particularly at six and 12
months. At six months, both systolic and diastolic blood pressure
was 2.1 mm Hg lower in the valsartan-treatment arm and still
significantly lower at 12 months.

The editorialists point out that two previous studies--the Systolic
Hypertension in Europe trial and the Valsartan Antihypertensive Long-
term Use Evaluation (VALUE) study--showed that immediate vs delayed
blood-pressure lowering translates into early benefit and that
narrowing the gradient between the treatment arms did not erase this
initial benefit. Other observational studies, they add, showed that
small differences in blood pressure explained most of the
cardiovascular outcomes. Staessen and Richart point out that
survival curves in the Jikei Heart study diverged early after
randomization and continued to do so even when the difference in
blood pressure was minimized or even abolished.

"The key question, then, is whether after the publication of the
Jikei Heart Study the increase in knowledge will be large enough to
benefit patients with hypertension, coronary heart disease, or heart
failure, particularly Japanese patients," they write. "The answer is
no, if marketers would spread the message that valsartan, or for
that matter other ARBs, might confer benefits beyond blood-pressure
lowering. Indeed, comprehensive reviews of the literature do not
support this point of view."

Instead, the take-home message, conclude Staessen and Richart, is
that aggressive antihypertensive treatment is safe and prevents
cardiovascular outcomes. Aggressive, in this case, means the
optimization of combination therapy, with each drug prescribed at
the lowest dose to attain targets and improve tolerance.


Mochizuki S, Dahlöf B, Shimizu M et al. Valsartan in a Japanese
population with hypertension and other cardiovascular disease (Jikei
Heart Study): a randomized, open-label, blinded end point morbidity-
mortality study. Lancet 2007; 369:1431-1439.
Staessen JA, Richart T. Sum and Substance in the Jikei Heart Study.
Lancet 2007; 369:1407-1408.

Diabetics with multivessel coronary artery disease (CAD) have similar
outcomes after placement of drug-eluting stents (DES) or coronary
artery bypass graft (CABG) surgery, according to a report in the
March 15th American Journal of Cardiology.

"The SYNTAX score may represent a more appropriate tool to better
define the complexity of CAD," Dr. Carlo Briguori from San Raffaele
Hospital, Milan, Italy told Reuters Health. In patients with low
SYNTAX score, the percutaneous approach seems to be a good
alternative to CABG.

Dr. Briguori and colleagues evaluated the effect of DESs versus off-
pump CABG (OPCABG) on 1-year outcomes in diabetic patients with
multivessel CAD and critical stenosis involving the proximal left
anterior descending coronary artery who underwent elective myocardial
revascularization.

The in-hospital stay was significantly longer in the 149 patients in
the CABG group (mean, 11 days) than in the DES 69 patients (mean, 4
days), the authors report.

The unadjusted in-hospital rate of cerebrovascular events and renal
failure was similar in the two groups.

The cumulative rate of major adverse cerebrovascular and cardiac
events (MACCE) at 12 months was somewhat higher in the DES group
after adjustment for known risk factors, the results indicate, but
there was no difference in the composite end point of death,
myocardial infarction, and cerebrovascular events at 12 months.

In both groups, diabetic retinopathy independently predicted MACCEs,
the report indicates. A high SYNTAX score and diabetic retinopathy
were additional risk factors in the DES group, whereas renal failure
requiring dialysis added to the risk in the CABG group.

"Screening diabetic patients for both nephropathy and retinopathy
prior to myocardial revascularization appears to be an effective way
to risk-stratify this group of patients and thus to focus preventive
measures," Dr. Briguori said.

"Furthermore, strict glycemic and lipid control and multifactorial
pharmacological intervention may improve outcome in this high-risk
group of patients," he added.

"We think that diabetic patients treated by DES implantation should
have scheduled angiographic follow-up, even though the conventional
non-invasive tools are acceptable," Dr. Briguori said. "This more
aggressive approach will help us in identifying patients at higher
risk, and, probably, improve long-term outcome."

"We are investigating the long term outcome (<3 years), in order to
address the compelling problem of late and very-late stent thrombosis
following DES implantation," Dr. Briguori added. "Recent data suggest
that diabetic patients represent a population at higher risk."

Am J Cardiol 2007;99:779-784

Improvements in depressive symptoms are not associated with
improvements in glycemic control in diabetic patients, according to a
report in the current issue of Psychosomatic Medicine.

"While clinical depression should be treated in all patients,
treating depressed mood (non-clinical depression) in patients with
type 2 diabetes as a strategy to improve glycemic control is not
effective," Dr. Richard S. Surwit from Duke University Medical
Center, Durham, North Carolina told Reuters Health.

Dr. Surwit and associates investigated whether changes in affective
symptoms after cognitive behavior therapy would differentially affect
glycemic control in 28 patients with type 1 diabetes and 62 with type
2 diabetes. Twenty-one type 1 diabetes patients and 44 type 2
patients completed the 12-month follow-up period.

Overall, changes in depression symptoms, as measured by Beck
Depression Index (BDI), did not affect HbA1c level or fasting blood
glucose concentration, the authors report.

Similarly, although post-treatment Hamilton Depression Scale values
improved for all patients, these improvements were not matched by
improvements in HbA1c or fasting blood glucose.

Even among the subgroup of 17 patients with clinical depression, the
researchers note, there was no evidence of an improvement in HbA1c
level as depression improved.

"The working hypothesis of the present study was that improving
depression through cognitive behavior therapy would differentially
impact patients with type 1 and type 2 diabetes," Dr. Surwit
said. "Therefore, the finding that significantly improving BDI with
cognitive behavior therapy failed to impact HbA1C in either type 1 or
type 2 patients was somewhat of a surprise."

"We are currently investigating the relationship between depression
and the onset of diabetes in a large longitudinal sample of Viet Nam
veterans," Dr. Surwit added. His team is also "studying the effects
of hostility, a personality construct with some overlap with
depression, on glycemic control in various non-diabetic populations."

Psychosom Med 2007;69:235-241.

Ruboxistaurin, which specifically inhibits protein kinase C (PKC)-
beta over-activation, improves skin microvascular blood flow and
symptoms of diabetic peripheral neuropathy, according to a report in
the April issue of Diabetes Care.

"The ultimate treatment of symptomatic (or even asymptomatic)
neuropathy must be designed to address the underlying pathogenetic
mechanisms...if we are to impact the underlying disease process and
not simply apply a band aid," Dr. Aaron I. Vinik from Eastern
Virginia Medical School, Norfolk, told Reuters Health.

Dr. Vinik and colleagues evaluated ruboxistaurin's effect on skin
microvascular blood flow and on secondary endpoints (sensory
symptoms, neurological deficits, quality of life, and others) in 40
diabetic patients with peripheral neuropathy.

Skin microvascular blood flow in the distal calf (but not in the
proximal calf) improved by 78.2% after treatment with ruboxistaurin,
compared with 22.5% in the placebo group, the authors report.

Sensory symptoms also improved significantly, the results indicate,
but the improvements in neurological deficits did not reach
statistical significance.

The quality of life score improved by 41.2% in the ruboxistaurin
group, the researchers note, a significant difference from the 4.0%
improvement in the placebo group.

There were no differences between the groups in other efficacy
measures, the report indicates, and there were no significant
differences in adverse events.

"Treatment of patients with neuropathy with the isoform-specific PKC-
beta inhibitor ruboxistaurin may reduce sensory symptoms and improve
endothelial-dependent skin blood flow," the investigators write.

"It has been hypothesized that changes in other measures of diabetic
peripheral neuropathy may occur after longer periods of ruboxistaurin
treatment," the researchers add. "Further placebo-controlled studies
of longer duration would be necessary to confirm this hypothesis."

"The natural history of diabetic neuropathy is changing and the rates
of deterioration once seen are disappearing," Dr. Vinik added, most
likely due to the availability and use of more drugs. "Thus, large
scale, multicenter studies that run for 3-4 years will be necessary
for the ultimate proof of principle."

Diabetes Care 2007;30:896-902

The use of protease inhibitors, a potent antiretroviral medication
used in the treatment of human immunodeficiency virus (HIV), is
associated with an increased risk of MI, a finding that is only
partly explained by dyslipidemia [1]. There was, however, no such
association with nonnucleoside reverse-transcriptase inhibitors
(NNRTIs), although investigators caution that experience with these
newer drugs remains limited.

"Using a data set that has accrued almost three times more end points
in the three years of follow-up since the last report, we continue to
observe an association between exposure to combination antiretroviral
therapy and the risk of myocardial infarction," write the Data
Collection on Adverse Events of Anti-HIV Drugs (DAD) study group in
the April 26, 2007 issue of the New England Journal of Medicine. This
relationship, write the authors, between exposure to protease
inhibitors and MI remained significant after multivariable adjustment.

Dr James Stein (University of Wisconsin Medical School, Madison, WI),
who wrote an editorial accompanying the DAD study [2], stressed that
the protease inhibitors have had a profound effect on survival,
turning HIV infection from a "short-term illness with a terrible
prognosis to a chronic illness that people can live with for more
than two decades."

However, when the protease inhibitors first came to market, there
were several case reports of young patients with heart disease and
stroke, as well as talk about an impending epidemic of cardiovascular
disease in the HIV population, as these drugs are associated with
central obesity, dyslipidemia, and insulin resistance.


"The question that physicians have struggled with for more than 10
years is just how big of a risk is this and how it affects our
patients," Stein told heartwire. "The overriding principle, however,
for any patient with HIV is that aggressive control of HIV is much
more important than the risks of its treatment for cardiovascular
disease."

The DAD study group

The DAD study, led by steering committee chair Dr Jens Lundgren
(University of Copenhagen, Denmark), is an international
collaboration of investigators following 23 437 HIV-infected patients
at 188 clinics in Europe, the US, and Australia. All participants are
actively followed in their cohorts from the time of enrollment--
December 1999 through April 2001--with an analysis assessing the risk
of MI prespecified once sufficient events had accumulated.

From data collected through February 2005 from the observation
cohorts, the analysis revealed that 345 patients had had an MI. The
incidence of MI increased from 1.53 per 1000 person-years in those
not exposed to protease inhibitors to 6.01 per 1000 person-years in
those exposed to the drugs for more than six years.

After adjustment for exposure to the other drug class--patients are
treated with more than one antiretroviral--and cardiovascular risk
factors, excluding lipid levels, patients receiving protease
inhibitors had an increase in the risk of MI of 16% per year, as
compared with an increase of only 5% per year among those treated
with NNRTIs. Further adjustment for serum lipid levels, hypertension,
and diabetes mellitus reduced this risk to 10% per year for those
treated with protease inhibitors and to zero among those treated with
the NNRTIs.

Protease inhibitors are known to increase total cholesterol and LDL
cholesterol to a greater extent than NNRTIs, the authors point out,
whereas the NNRTIs are known to increase HDL cholesterol. However,
the risk of MI associated with protease inhibitors was not fully
explained by the lipid changes induced by the drug class.

"Thus, the full mechanism by which protease inhibitors may lead to
increase rates of myocardial infarction remains to be elucidated,"
conclude the DAD investigators.

Risk with the drugs is still very small

Stein, the NEJM editorialist, told heartwire that the magnitude of
risk observed with protease inhibitors is not high, especially when
compared with other cardiovascular risk factors. The risk, for
example, is still less than being male, being a smoker, having
diabetes mellitus, or having had a previous cardiovascular event.

"The risk is there, but it's still very small," said
Stein. "Treatment leads to risk factors that need to be managed, but
this shouldn't for one minute discourage people from treating HIV
aggressively. I would also say that there is not an epidemic of heart
disease on the horizon. When you look at the absolute risks of the
people in these studies--mostly men in their early 40s--the risk is
low to moderate depending on how many risk factors they have. This
risk is mostly attributable to their smoking, their male sex, and
their history of heart disease. We can intervene on smoking as well
as on lipids, so this should remain our focus."

New guidelines will soon be published by the HIV Medical Association,
a branch of the Infectious Disease Society of America, for diagnosis
and management of dyslipidemia in patients with HIV, said Stein.

Regarding the possibility that NNRTIs do not significantly increase
the cardiovascular risk, Stein said it is interesting and plausible,
although such a finding is not proven by this study. The drugs do
have fewer adverse lipid effects than the protease inhibitors, but
the limitations of the study prevent definitive conclusions. The main
limitation is the person-years of exposure with the drugs, with just
63.7% patients exposed to the NNRTIs for a median of 2.6 years, as
compared with 93.6% of patients exposed to the protease inhibitors
for almost seven years.

"At this point, I don't think cardiovascular risk should be a
deciding factor when an HIV doctor is choosing a class of drug for
treatment," he said. "The overriding factor should be what the best
drug is for their HIV."

Boston study shows risk of MI doubles in HIV-positive patients

A second study, published by lead author Dr Virginia Triant (Brigham
and Women's Hospital, Boston, MA), published online April 24, 2007 in
the Journal of Clinical Endocrinology & Metabolism, has also shown a
significant association between infection with HIV and risk of MI
[3]. While rates of several cardiovascular risk factors were also
increased in study participants infected with HIV, the increased
incidence of MI was beyond what could be explained by risk-factor
differences, write the authors.

Using the Research Patient Data Registry, a database of demographic
and diagnostic information on patients treated at Massachusetts
General Hospital and Brigham and Women's Hospital, investigators
compared information on almost 4000 HIV-infected patients with data
from more than one million patients without HIV.

Across all age groups, the risk of MI was markedly higher for those
infected with HIV. Although traditional cardiovascular risk factors,
including dyslipidemia, diabetes, and hypertension, were more common
among the HIV-infected patients and did account for some increased
risk, the increased risk for MI associated with HIV remained
significant even when adjusted for those risk factors. Overall, the
risk was almost doubled in those with HIV and was almost tripled
among HIV-positive women.

"Determining the mechanisms of increased cardiovascular disease and
cardiac risk-factor rates in HIV-infected women is an important area
of future research," conclude the authors. "Cardiac risk-modification
strategies are also particularly needed and will be an important
component of the long-term care of this population."

The DAD study group. Class of antiretroviral drugs and the risk of
myocardial infarction. N Engl J Med 2007; 356: 1723-1735.
Stein JH. Cardiovascular risks of antiretroviral therapy. N Engl J
Med 2007; 356: 1773-1775.
Triant VA, Lee H, Hadigan C, Grinspoon SK. Increased acute myocardial
infarction rates and cardiovascular risk factors among patients with
HIV disease. J Clin Endocrinol Metab 2007; DOI: 10.1210/jc.2006-2190.
Available at: http://jcem.endojournals.org.

A technology-driven claims-based clinical alert system can identify
gaps in care and improve implementation of guidelines for calcium,
phosphorus, or parathyroid hormone (PTH) monitoring in patients with
chronic kidney disease (CKD), according to a presentation at the
National Kidney Foundation (NKF) annual meeting held in Orlando,
Florida, from April 10-14.

"Although there are several recent clinical practice guidelines in
nephrology, not much information exists regarding patient and
physician compliance with their recommendations," presenter and lead
author Daniel Halevy, MD, medical director of ActiveHealth
Management in New York City, told Medscape. "We are able to use a
computerized system to analyze both clinical and administrative
patient data to determine whether these guidelines are being
followed. If a patient is identified who has not undergone the
appropriate testing or treatment, the system can act on the
information by alerting the individual's physician to the specific
deficit for that patient."

Although the Kidney Disease Outcomes Quality Initiative (KDOQI)
Clinical Practice Guidelines were developed by the NKF to help guide
the management of CKD patients, surveys of current clinical practice
continue to identify quality-of-care deficits. In patients with CKD
stages 3 and 4, estimates of PTH testing range from 1% to 30%,
falling far short of the KDOQI recommendations.

Dr. Halevy's group developed a claims-triggered clinical alert and
reminder system to communicate potential clinical opportunities to
the primary care provider, using messages derived from the recent
KDOQI guidelines regarding calcium, phosphorus, and PTH monitoring
in CKD patients. Once the alert was issued, the investigators
measured compliance with the guideline recommendations using claims-
based data during a preestablished evidence time window.

During the study period from November 2005 through June 2006,
patients with CKD stages 3 and 4 received 470 and 193 alerts per
100,000 patient-years of enrollment, respectively. Objective
evidence of implementation of calcium, phosphorus, or PTH monitoring
after delivery of the alert message was present in 40% of stage 3
CKD patients and in 47% of stage 4 CKD patients.

"The results demonstrate that we can use technology to screen data
from millions of patients, identify thousands of patients not
receiving guideline-recommended care, and then successfully close
these gaps in care more than 40% of the time by communicating a
patient-specific alert to their physician," Dr. Halevy said. "This
approach can be applied to all areas of medicine to promote the
practice of guideline-recommended and evidence-based care."

Ron Wald, MD, an assistant professor of nephrology at St. Michael's
Hospital and the University of Toronto in Ontario, Canada, was not
involved with this study, but was asked by Medscape to provide
independent commentary.

"This study demonstrates that clinical reminders may help physicians
in adhering to recommended guidelines," Dr. Wald said. "Although the
ability to change physician behavior is encouraging, it is unclear
if these behaviors lead to improved mineral metabolic control for
the patients."

Dr. Wald described the K/DOQI guidelines for mineral metabolism
as "largely opinion-driven," particularly with regard to the
monitoring of mineral metabolic parameters and the choice of targets
in the predialysis CKD population that were evaluated in this study.

"While it is likely a good thing to see physicians become more
diligent at checking the values of these markers, it is unclear if
this will lead to better patient outcomes," Dr. Wald
explained. "Moreover, it is unclear to what extent mineral metabolic
abnormalities should be treated in CKD stages 3 and 4."

A study by Dr. Wald and colleagues published in the February issue
of the American Journal of Kidney Diseases (2007;49[2]:257-266)
looked at the impact of the KDOQI Clinical Practice Guidelines for
Bone Metabolism and Disease in a large dialysis network. They
compared albumin-adjusted serum calcium, phosphate, calcium x
phosphorus product, and PTH values in patients undergoing
hemodialysis during 8-month periods before (n = 9516) and after (n =
9543) release of the KDOQI guidelines in  October 2003. After
release of the guidelines, there was a modest decrease in mean per-
patient concentration for all mineral metabolic indicators, and the
proportion of values within target ranges for serum calcium,
phosphate, and calcium x phosphorus product increased, but values
remained unchanged for PTH.

"In a hemodialysis population, despite regular protocolized testing
of mineral metabolic markers as is usual in such patients, overall
adherence to K/DOQI  targets was weak," Dr. Wald said. "The next
question to answer is now that MDs are more proficient at monitoring
relevant bloodwork in predialysis CKD, will this lead to better
mineral metabolic control for patients?"

Dr. Wald's additional suggestions for future research are to
determine: (1) optimal mineral metabolic targets for patients with
predialysis CKD; (2) the levels of calcium, phosphate, calcium x
phosphorus product, and PTH that are associated with adverse
outcomes in this population; and (3) whether correction of these
abnormalities leads to improved outcomes.

"Several studies have identified quality-of-care gaps and large
inefficiencies in current clinical practice, [and] both the
government and private payors are pushing forward to address these
gaps and inefficiencies through the use of performance metrics and
pay-for-performance initiatives," Dr. Halevy concluded. "However,
it's not enough to identify these gaps without a system to help
correct them. We have demonstrated that not only can such a system
be used to identify patients with care deficits, but also that
communicating with physicians can lead to improved implementation of
the guidelines."

There were no external sources of funding for this project, and the
authors report no financial conflicts of interest. Dr. Wald is the
recipient of a research fellowship from Amgen.

NKF 2007 Spring Clinical Meetings: Abstract 46. April 10-14, 2007

A high titer of autoantibodies to GAD identifies a specific
phenotype of adult-onset autoimmune diabetes, Italian researchers
report in the April issue of Diabetes Care.

"Our findings," lead investigator Dr. Raffaella Buzzetti told
Reuters Health, "indicate that both autoimmunity and insulin
resistance may contribute to the pathogenesis of diabetes in adults
with a variable degree of synergism, as reflected by titers of GAD
antibodies."

Dr. Buzzetti of La Sapienza University, Rome and colleagues note
that slowly progressive autoimmune diabetes in adults is often
indistinguishable from classic type 2 diabetes.

Patients with autoimmune diabetes, they add, are usually diagnosed
via the presence of antibodies to GAD (GADAs), with or without
associated cytoplasmic islet cell antibodies and protein tyrosine
phosphatase IA-2 antibodies (IA-2As).

To investigate further, the team examined data from 4,250 type 2
diabetic patients and found that 4.5% had GADAs or IA-2As or both.

The patients with autoimmune diabetes showed a clinical phenotype
significantly different from that of type 2 diabetes, including
higher fasting glucose and A1C and lower BMI and uric acid.

In addition, compared with those with low GADA titers, patients with
high GADA titers had more prominent traits of insulin deficiency, a
profile of more severe autoimmunity, and a lower prevalence of
metabolic syndrome.

In light of these findings, the researchers conclude that there are
patients with a "high GADA titer in which the autoimmune process is
presumably strong enough to induce diabetes with no major
contribution by other concomitant factors and a second group with
low GADA titers, reflecting a less intense autoimmune process, with
associated features of insulin resistance."

Diabetes Care 2007;30:932-938.

A multidisciplinary team of researchers finds no evidence to support
the widely held view that the "thrifty genotype" theory explains
racial differences in the prevalence of obesity and type 2 diabetes
mellitus (T2DM).

The thrifty genotype theory posits that humans developed a genotype
to efficiently absorb and store nutrients to cope with feast-famine
cycles, but this has become maladaptive in affluent and sedentary
societies.

However, there is nothing "to suggest that minority populations are
especially genetically susceptible" to obesity, and consequently
T2DM, when energy is abundant, the researchers say.

The team, led by anthropologist Dr. Michael Montoya, of the
University of California at Irvine, report their findings in a paper
titled "Racialized Genetics and the Study of Complex Diseases,"
published in the Spring issue of Perspectives in Biology and
Medicine.

"Genetics plays a role (in the development of T2DM) -- it does in
everything," Dr. Montoya told Reuters Health, "but 90-plus-percent
can be explained by environmental causes."

What appears to play a much bigger role "is poverty, housing
segregation, education, nutrition ... and access to health care," he
asserted.

"The research community for many years has been looking for genetic
causes to explain ethnic differences," he said. "They have been so
focused on genetics that they have lost the big picture."

"Genes specific to a group that account for a disease do not mean
that those genes cause the disease," Dr. Montoya explained. "The
differences can be explained through nongenetic factors ... In fact,
the vast majority can be explained by nongenetic causes."

In their paper, Dr. Montoya and colleagues call for an
interdisciplinary approach to genetic epidemiologic research.

"Genetic epidemiological researchers need to move beyond the mere
recognition of ethnorace as socially constructed and towards the
practice of studying ethnoracial health disparities as the
biological embodiment of sociopolitical processes," Dr. Montoya and
colleagues argue.

The challenge, they conclude, is to link "population health
parameters, including environmental exposures and social conditions,
with both pathophysiology and genetic risk estimates."

Perspect Biol Med 2007;50:203-227.

The MERLIN TIMI-36 trial, which showed no effect of ranolazine
(Ranexa, CV Therapeutics) on outcomes in non-ST-elevation-ACS
patients but did provide reassuring safety and efficacy data on its
use in stable angina, has now been published in the April 25, 2007
issue of the Journal of the American Medical Association [1]. The
trial was first presented at last month¡¦s American College of
Cardiology meeting.

MERLIN-TIMI 36 enrolled 6560 non-ST-elevation-ACS patients within 48
hours of ischemic symptoms who were treated with ranolazine or
placebo and followed up for a median of 348 days. The primary
efficacy end point was a composite of cardiovascular death, MI, or
recurrent ischemia through the end of the study. This was not
significantly different between the two groups. There was also no
difference in other major composite outcome end points, but there
was a significant reduction in recurrent ischemia in the ranolazine
group.

The other main focus of the trial was safety, given that ranolazine
is associated with prolongation of the QT interval. In the trial,
QTc prolongation requiring a reduction in the dose of intravenous
drug occurred in 31 patients (0.9%) receiving ranolazine, compared
with 10 patients (0.3%) receiving placebo. Symptomatic documented
arrhythmias did not differ between the two groups, and there was
also no difference in total mortality. And there was actually a
significant reduction in arrhythmias detected on Holter monitoring
during the first seven days of treatment with ranolazine.

Because of concerns over the prolongation of the QT interval,
ranolazine was initially approved only for the treatment of selected
patients with chronic angina who have persistent symptoms despite
treatment with beta blockers, calcium-channel blockers, or nitrates.
The authors of the paper, led by Dr David Morrow (Brigham and Women¡¦
s Hospital, Boston, MA), state that the results of the MERLIN trial
¡§do not support the use of ranolazine for acute management of ACS
or as disease-modifying therapy for secondary prevention of
cardiovascular death or MI." But they add: ¡§Our findings suggest a
benefit of ranolazine as antianginal therapy in a substantially more
broad population of patients with established ischemic heart disease
than previously studied." Noting that previous smaller studies of
the drug have pointed to a possible diminished treatment effect of
ranolazine on exercise performance in women, the researchers note
that, in the MERLIN trial, ¡§the reduction in recurrent ischemia
with ranolazine was certainly not less in women than in men."

Adverse-effect profile

On the adverse effects of the drug, Morrow et al note that while
there was no excess of arrhythmias with ranolazine, there was a
higher rate of discontinuation due to adverse events in the
ranolazine group, with the most common adverse events being
dizziness, nausea, and constipation. ¡§This tolerability profile,
along with the higher proportion of patients with syncope, should be
considered by the clinician in assessing the potential risks vs
benefits of treatment with ranolazine," they write.

They add that the reduction in arrhythmias detected on Holter
monitoring with ranolazine provides the first clinical evidence for
the potential relevance of experimental data showing suppression of
markers of proarrhythmia and provides some reassurance with respect
to arrhythmia as a potential cause for syncope. They note that the
possible antiarrhythmic effects of ranolazine warrant additional
investigation.

Ranolazine: A good backup option

In an accompanying editorial, Drs Kristin Newby and Eric Peterson
(Duke University Medical Center, Durham, NC) say that beta blockers
and nitrates should still be considered initial therapies for
angina, but that the enhanced safety information and supportive
antianginal data from MERLIN suggest that ranolazine may offer a
backup option for intensification of antianginal treatment if these
first-line agents fail [2].

Press telebriefing: MERLIN and COURAGE together show broader role
for ranolazine


A press telebriefing sponsored by CV Therapeutics gathered together
MERLIN investigators, one of the JAMA editorialists, and Dr William
Boden, the chief investigator of the landmark COURAGE trial, which
showed no benefit of PCI over optimal medical therapy in preventing
future events in patients with stable coronary disease.

Chairing the briefing, Dr Eugene Braunwald, senior author of the
MERLIN-TIMI 36 trial, noted that the recent COURAGE trial has
highlighted the role of medical therapy, rather than PCI, as first-
line treatment of stable angina and that despite the availability of
many different antianginal therapies, there are still many millions
of patients who remain symptomatic.

Confirming this, Boden noted that, even after five years of
aggressive medical therapy in the COURAGE study, around 25% of
patients still had symptoms, regardless of whether they had
undergone PCI or not. ¡§This highlights the need for new medical
treatments, and the MERLIN trial is therefore welcome news in that
it supports the safety and benefits of ranolazine, the first new
antianginal in 35 years," he said. He suggested that ranolazine may
be particularly appropriate for older patients, who tend to be less
tolerant of multiple drugs that affect heart rate and blood
pressure, as ranolazine does not have any such effects. And older
patients tend to have worse renal function and are therefore more
susceptible to adverse effects from the dye used in angiography,
which is another reason not to rush to PCI in this group, he added.

The editorialist, Newby, described the COURAGE and MERLIN studies as
¡§a tremendous pair of trials¡¨ that help frame the current
treatment approach to patients with chronic heart disease. ¡§COURAGE
showed that PCI does not extend life and does not add much to best
medical therapy but can be used as a backup. But even with best
medical therapy, patients were still having symptoms and events, and
the door is wide open for new therapies. Ranolazine can therefore be
regarded as another treatment in our arsenal now that the safety
concerns have been addressed. While I still think beta blockers
should be used first, as they have a proven outcome benefit, many
patients have side effects with beta blockers, and other treatments
are often necessary on top of beta blockers, so it's nice to know we
now have another option to further intensify therapy," she
commented.

Morrow DA, Scirica BM, Karwatowska-Prokopczuk E, et al. Effects of
ranolazine on recurrent cardiovascular events in patients with non-
ST-elevation acute coronary syndromes. The MERLIN-TIMI 36 randomized
trial. JAMA 2007; 297:1775-1783.
Newby LK and Peterson ED. Does ranolazine have a place in the
treatment of acute coronary syndromes? JAMA 2007; 297:1823-25.

A new predictive index with a simplified scoring system, one that is
readily available from preoperative information, is able to
discriminate between patients at low and high risk for renal-
replacement therapy following cardiac surgery and can be used to
provide accurate prognostic information on those at risk for acute
renal failure following surgery [1].

"There are a lot of predictive indices out there, not just in renal
failure, but in general," said lead investigator Dr Duminda
Wijeysundera (University of Toronto, ON). "If you develop a very
accurate predictive index, but one that is relatively complex,
you've certainly achieved something great from a research
perspective, but is it really going to impact clinical practice or
research design? People are less likely to use something that is
more complex. Our goal was to try to come up with a reasonably sized
set of variables and a scoring system that was quite simple to use."

The simplified scoring system for estimating risk of postoperative
renal failure includes eight variables, explained Wijeysundera, all
of which can be measured accurately prior to cardiac surgery. The
scoring scheme, derived from more than 10 000 patients undergoing
cardiac surgery and validated in two separate cohorts, is now
published in the April 25, 2007 issue of the Journal of American
Medical Association.

Increasing prevalence of renal failure following cardiac surgery

In an interview with heartwire, Wijeysundera explained that while
renal failure following cardiac surgery is not common--even in this
retrospective cohort study, more than half of patients were
eventually classified as low risk--there is a belief that renal-
replacement therapy will become more common in the future.

"When you look at the demographics of individuals undergoing cardiac
surgery these days, procedures, typically, are less often isolated
CABG procedures and tend to be combined procedures," said
Wijeysundera. "With the growing use of PCI, patients undergoing
cardiac surgery also tend to be older and have more comorbidity. I
think there are some indicators to suggest that prevalence of
dialysis after cardiac surgery is increasing, and when this occurs,
there are implications for patient mortality, morbidity, and cost."

To develop a simplified predictive scoring index for preoperatively
classifying at-risk patients, investigators retrospectively studied
20 131 patients who underwent cardiac surgery. The derivation cohort
consisted of 10 751 patients at Toronto General Hospital who
underwent surgery between 1999 and 2004, while the validation cohort
consisted of 2566 patients at the same hospital undergoing cardiac
surgery between 2004 and 2005 and an additional 6814 patients at
Ottawa Heart Institute undergoing surgery between 1999 and 2003.

From the derivation cohort, multivariable predictors of the need for
renal replacement included estimated glomerular filtration rate
(eGFR), diabetes mellitus requiring medication, left ventricular
ejection fraction <40%, previous cardiac surgery, type of procedure,
urgency of surgery, and the use of preoperative intra-aortic balloon
pump. The predictive index was scored from 0 to 8 points, with all
components assigned one point except for estimated glomerular
filtration rate <30 mL/min, which was assigned two points.

Among the 53% of patients with low-risk scores (<1), the risk of
renal-replacement therapy was 0.4%. In contrast, among the 6% of
patients with high-risk scores (>4), this risk was 10%. The
stability of the scoring system to differentiate between high-,
intermediate-, and low-risk patients was consistent, with areas
under the receiver operating characteristic curve in the derivation,
Toronto validation, and Ottawa validation cohorts of 0.81, 0.78, and
0.78. In a comparison with other risk indices, Wijeysundera said two
older indices performed comparably but pointed out that these
scoring schemes are more complex and include more variables.

"From a clinician's perspective, the simplified scoring index will
allow them to rationalize whatever renal-protective strategies they
choose to use," said Wijeysundera. "The vast majority of patients
undergoing cardiac surgery are low risk for renal replacement, and
these are patients where we really don't need to do anything
specific to reduce their risk. We can treat them as we would
normally. Then there are the other patients, those at intermediate
and high risk, where we could rationalize using a renal-protective
therapy."

Those at intermediate risk, for example, might benefit from strict
control of intraoperative hematocrit, off-pump CABG, or fenoldopam,
as well as close postoperative surveillance of early renal-injury
biomarkers. Identifying high-risk patients will also assist in the
allocation of postoperative resources, as well as benefit patients
by providing a more accurate estimate of risk. Equally important,
the risk index could aid in the design of future studies, said
Wijeysundera.

"One of the big problems with the design of studies is that there is
no point studying therapies to prevent renal failure in patients who
are unlikely to get it," he said. "Study sizes would be very large
and chances are that it wouldn't likely have an effect on a low-risk
population. . . . From a research perspective, there have to be
better ways to identify at-risk patients before surgery so that we
can actually target them for clinical trials."

Wijeysundera DN, Karkouti K, Dupuis JY, et al. Derivation and
validation of a simplified predictive index for renal replacement
therapy after cardiac surgery. JAMA 2007: 297:1801-1809.

Pulsus paradoxus is no longer a paradox, but it may be among the
most reliable of the traditional clinical signs suggesting cardiac
tamponade "when faced with a patient with pericardial effusion and
the echo is equivocal," observed Dr Christopher L Roy (Brigham and
Women¡¦s Hospital, Boston, MA).

The lead author of an analysis that explores the evidence base for
the classic history, clinical examination, and lab workup in such
cases, which appears in the April 25, 2007 issue of the Journal of
the American Medical Association [1], Roy told heartwire that
there's little out there. On the other hand, he said, what evidence
there is points to a decent level of sensitivity, if not
specificity, for several of the traditional signs.

"Based on our review of the literature, dyspnea, tachycardia,
elevated jugular venous pressure, pulsus paradoxus, or cardiomegaly
on chest radiograph is seen in 70% or more of patients with a known
pericardial effusion and cardiac tamponade," Roy et al write. One
study suggests that "a pulsus paradoxus greater than 10 mm Hg
increases the likelihood of cardiac tamponade, while a pulsus
paradoxus of 10 mm Hg or less decreases the likelihood." Moreover,
they write, "the presence and degree of pulsus paradoxus may be
helpful to predict the degree of hemodynamic compromise" in such
patients with suspected tamponade.

The analysis can be viewed as "codifying the clinical gestalt,"
according to Roy, such that "in an absence of those findings, you
might be able to avoid an echo in some patients." But that's a leap,
he said, because all of the studies in the analysis included
patients with echo-identified pericardial effusion.

Roy CL, Minor MA, Brookhart MA, Choudhry NK. Does this patient with
a pericardial effusion have cardiac tamponade? JAMA 2007; 297:1810-
1818.

A major phase 3 development program has been announced for Schering-
Plough¡¦s new oral antiplatelet agent, involving two of the most
prominent clinical-trial centers in the US [1].

The product, known as TRA-SCH 530348, is the first of a new class of
agents. It blocks the platelet PAR-1 receptor to which thrombin
binds, thus inhibiting thrombin-induced activation of platelets, and
is therefore classified as a thrombin-receptor antagonist (TRA).

In a phase 2 trial, reported at the American College of Cardiology
meeting last month, the compound showed a trend toward fewer
ischemic events without increasing bleeding when added to standard
antiplatelet therapy with aspirin and clopidogrel in patients
undergoing PCI. If phase 3 trials confirm that the drug does
actually reduce ischemic events without increasing bleeding, TRA-SCH
530348 would be a surefire winner. But that is a big if, and many
previous drugs have shown promising results in phase 2 trials that
have not been borne out in larger studies.

Two major phase 3 trials with TRA-SCH 530348 are now planned, one
for the treatment of acute coronary syndrome (ACS) patients, and one
for secondary-prevention in patients who have had a prior MI or
stroke or who have existing peripheral arterial disease. In both
trials, TRA-SCH 530348 will be compared with placebo, and all
patients will be taking standard antiplatelet therapy (including
aspirin and clopidogrel). The trials will be conducted in
approximately 30 countries at more than 800 sites for each trial.

The ACS trial will involve approximately 10 000 patients. TRA-SCH
530348 will be given once daily with a 40-mg oral loading dose and a
2.5-mg oral maintenance dose. The primary end point is the composite
of cardiovascular death, MI, rehospitalization for ACS, urgent
coronary revascularization, or stroke. Patients will be followed for
a minimum of one year. This trial is being conducted by the Duke
Clinical Research Institute under the leadership of Dr Robert
Harrington.

The secondary prevention study, known as the TRA 2P-TIMI 50 trial,
will involve approximately 19 500 patients with prior MI or stroke
or existing peripheral arterial disease. This trial will evaluate a
2.5-mg daily maintenance dose of the drug. The primary end point of
the trial is the composite of cardiovascular death, MI, urgent
coronary revascularization, or stroke. Patients will be followed for
a minimum of one year. This trial is being conducted by the TIMI
Study Group, chaired by Dr Eugene Braunwald (Harvard Medical School,
Boston, MA).

Schering-Plough notes that the FDA has granted fast-track
designation to TRA-SCH 530348, which allows expedited review of
drugs and biologics for serious or life-threatening conditions that
demonstrate the potential to address unmet medical needs.

Schering-Plough. Schering-Plough announces initiation of two phase
III clinical trials for novel selective antiplatelet therapy (TRA-
SCH 530348) [press release]. April 18, 2007. Available at:
http://www.schering-plough.com/schering_plough/news/release.jsp?
releaseID=987054.

Use of insulin glargine for diabetes during pregnancy does not
increase the risk of fetal macrosomia or neonatal morbidity,
findings from a pilot study indicate.

In experimental studies, insulin analogues like insulin glargine
have been shown to have growth-promoting effects. Concerns have,
therefore, been raised that use of insulin glargine during pregnancy
could promote fetal macrosomia and other problems. A recent review
actually recommended against the use of the agent during pregnancy,
but called for further studies to investigate its safety.

As reported in the April issue of BJOG, Dr. N. Price and colleagues,
from John Radcliffe Hospital in Oxford, UK, examined this issue in
20 pregnant women with type I diabetes and 44 with gestational
diabetes. Half of the subjects used insulin glargine and half used
an intermediate-acting human insulin.

No significant differences in birthweight were noted between infants
born to insulin glargine users and those born to controls. In fact,
the incidence of fetal macrosomias was actually slightly lower in
the insulin glargine group: 37.5% vs. 40.6%.

The groups were also comparable in terms of neonatal complications,
admission to special care baby units, and congenital abnormalities,
the report indicates.

"We believe that our results justify large randomized trials to
confirm the efficacy and safety of insulin glargine in the treatment
of pregnant women with type I diabetes and those who develop
diabetes during pregnancy," the authors conclude.

BJOG 2007;114:453-457.

Results of a randomized trial show a significant reduction in venous
thromboembolism (VTE) events in stroke patients receiving the low-
molecular-weight heparin enoxaparin (Lovenox, Sanofi-Aventis) vs
unfractionated heparin (UFH), without a significant increase in
clinically important bleeding.

These results, from the Prevention of VTE After Acute Ischemic
Stroke with LMWH Enoxaparin (PREVAIL) study, presented previously at
the American Society of Hematology 48th Annual Meeting and
Exposition and more recently at the American Stroke Association
International Stroke Conference 2007, are now published in the April
21 issue of the Lancet.

David G. Sherman, MD, from the University of Texas Health Science
Center, in San Antonio, was principal investigator of the trial,
which included patients from 15 countries.

"Enoxaparin is preferable to unfractionated heparin for venous
thromboembolism prophylaxis in this high-risk medically ill
population, in view of its better clinical benefits-to-risk ratio
and convenience of once-daily administration," the authors conclude.

Best Treatment Uncertain

Patients with acute ischemic stroke are at increased risk for VTE
events, including deep venous thrombosis (DVT) and pulmonary
embolism (PE). Without prophylaxis, up to 75% of patients with
hemiplegia after a stroke will develop DVT and 20% will develop PE,
which is fatal in 1% to 2% of patients, the researchers write.

Prophylaxis with either low-molecular-weight heparin or
unfractionated heparin is currently recommended in these patients.
However, they write, "prophylactic regimens used for patients with
stroke are quite varied, because many physicians remain uncertain
about the best treatment, and data from studies with high numbers of
patients are needed to resolve this issue."

PREVAIL was an open-label trial comparing the efficacy and safety of
enoxaparin vs unfractionated heparin in preventing VTE events in
patients with acute ischemic stroke confirmed by computed tomography
(CT) who had sufficient paralysis that they were unable to walk
unassisted.

A total of 1762 patients were enrolled within 48 hours of stroke
symptom onset and randomized to receive either 40 mg daily of
enoxaparin given subcutaneously or 5000 IU of heparin twice daily
for 10 days plus or minus 4 days ¡X depending on when the patient
was able to be ambulated. They were followed for a period of 90
days. Patients were also stratified by stroke severity according to
National Institutes of Health Stroke Scale (NIHSS) scores as severe
(14 or higher) and less severe (less than 14).

The primary efficacy end point was a composite of symptomatic or
asymptomatic DVT and symptomatic or fatal PE during the treatment
period. Safety end points included symptomatic intracranial
bleeding, major extracranial bleeding, and all-cause mortality. To
be included in the primary efficacy analysis, all patients must have
undergone a venogram or other imaging; of the 1762 patients
enrolled, 1335 were considered in the primary efficacy end point,
666 in the enoxaparin group and 669 in the unfractionated heparin
group.

Results showed a 43% reduction in the primary end point (risk ratio,
0.57; 95% CI, 0.44 ¡V 0.76; P = .0001, adjusted for NIHSS score)
with enoxaparin vs unfractionated heparin.

In terms of safety, the occurrence of any bleeding was similar
between groups, and the composite of symptomatic intracranial
hemorrhage (ICH) and major extracranial hemorrhage was "closely
similar," the authors note. There was no difference in symptomatic
ICH, but major extracranial bleeding was higher with enoxaparin.
Most of these were gastrointestinal bleeding events, they add, and
did not increase mortality.

In the past, treating physicians have had to make a choice at the
beside, typically between heparin and a low-molecular-weight
heparin ¡X enoxaparin being the most commonly used low-molecular-
weight heparin in the United States, Dr. Sherman told Medscape when
these results were first presented.

"Now, with the PREVAIL study, we have evidence from a single large
study that shows, in a very powerful way, that enoxaparin is more
effective in preventing clots than is unfractionated heparin. My
suspicion is that many treating physicians, if not most or all, will
select enoxaparin as their drug of choice for prevention of DVT and
pulmonary embolus, as opposed to unfractionated heparin."


The PREVAIL study was funded by Sanofi-Aventis, maker of enoxaparin.
Dr. Sherman is on the Sanofi-Aventis speakers' bureau and consulted
with Sanofi-Aventis on stroke-related research and educational
activities.

Lancet. 2007;369:1347-1355.

Hyperspectral technology (HT), which quantifies tissue oxygenation
in an anatomically relevant map, is able to predict healing of
diabetic foot ulcers, according to a report in the April issue of
Diabetes Care.

"By providing measurements of both oxyhemoglobin and
deoxyhemoglobin, we can understand both the oxygen delivery to and
oxygen extraction by the tissue," Dr. Aristidis Veves from Beth
Israel Deaconess Medical Center, Boston, Massachusetts told Reuters
Health. "For the first time we can actually get an understanding of
the adequacy of perfusion, not just whether there is blood flow to
the leg, but is there enough blood flow for the tissue to heal."

In their paper, Dr. Veves and colleagues explain that HT is a method
of scanning spectroscopy in which the wavelength of light admitted
to a sensor is varied, to provide a spectrum for each pixel. Local
tissue spectra are compared with standard spectra for relevant
chemicals.

"The hyperspectral system is fast and easy to use, so it can be
incorporated into the work flow and will be relevant in a practice
setting," Dr. Veves explained.

The researchers used HT to assess tissue oxygenation around diabetic
foot ulcers and evaluated the ability of this technique to predict
diabetic foot ulcer healing and progress of foot ulcers over a 6-
month period.

The researchers employed a HT healing index based on a linear
discriminant analysis that compared HT measurements of healing ulcer
sites and nonhealing ulcer sites.

All HT values differed significantly between subjects with
nonhealing ulcers, subjects with healed ulcers, the authors report.

Ulcer sites having a positive HT healing index at the first visit
were predicted to heal, and those having a negative HT index were
predicted not to heal. This approach yielded 93% sensitivity, 86%
specificity, 93% positive predictive value, and 86% negative
predictive value for ulcer healing.

"Until now, we were never able to reliably predict from a single
visit whether an ulcer would heal or not heal," Dr. Veves
said. "Previous studies in our unit indicated that we had to follow
the patients for four weeks to see if the ulcer was likely to heal.
If we know from the beginning that an ulcer is not likely to heal
with standard therapy, we can be more aggressive right away."

If the potential of hyperspectral technology is confirmed, he
added, "the technique can reduce the overall cost to the health care
system with improvement of ulcer care and decrease in amputations."

Diabetes Care 2007;30:903-910.

New data from a meta-analysis reviewing the effect of whole-grain
foods or diets on coronary heart disease (CHD) has shown that whole-
grain cereals can reduce CHD risk factors, with specific reductions
in total- and LDL-cholesterol levels [1]. The studies, however, are
small and of short duration, and, as a result, the effect of whole-
grains on CHD deserves further study, say investigators.

"While there is growing evidence from observational studies that
whole grains have benefits for coronary heart disease, there is
insufficient evidence available from randomized controlled trials
[RCTs] to make any conclusions about whole grains in general and
coronary heart disease, except whole-grain oats," writes lead
investigator Dr Sarah Kelly (University of Teesside, Middlesbrough,
UK) in the analysis, published online April 18, 2007 in the Cochrane
Database of Systematic Reviews. "There is some evidence from RCTs
that whole-grain oats can lower LDL- and total-cholesterol levels in
those with preexisting risk factors for CHD. This effect was seen at
four weeks for total cholesterol so may be effective even with short
interventions."

Further study is needed

Whole-grain and whole-meal cereal foods are grain foods that include
the outer layers of the grain, including the bran and germ.
Previously, there have been a few epidemiological studies that
examined the association between the intake of whole-grain foods and
risk of CHD, including the Iowa Women's Health Study and Nurses'
Health Study, with both of these studies showing a benefit with
whole-grain consumption.

The purpose of this review, write the authors, was to examine the
current evidence from RCTs to assess the relationship between whole-
grain-food consumption and the various effects on CHD mortality,
morbidity, and CHD risk factors in subjects with coronary disease or
those with risk factors for coronary disease.

In total, 10 studies were included in the meta-analysis, of which
eight trials studied the effects of whole-grain oats. The trials
were short-term, ranging from four to eight weeks in length, and
included a small number of patients. Overall, 914 subjects were
included in the meta-analysis. None of the studies identified
reported the effect of whole grains on CHD mortality or CHD events.
However, in seven of the eight studies using oats, significantly
lower LDL- and total-cholesterol levels were reported in those
randomized to the whole-grain arm. The absolute reduction in total
and LDL cholesterol was roughly 7 mg/L.

"Despite the consistency of the effects in trials of whole-grain
oats, the positive findings should be interpreted cautiously,"
conclude Kelly and colleagues. "Many of the trials identified were
short-term, of poor quality, and had insufficient power. Most of the
trials were funded by companies with commercial interests in whole
grains. There is a need for well-designed, adequately powered,
longer-term randomized controlled studies in this area. In
particular, there is a need for randomized controlled trials on
whole-grain foods and diets other than oats."

Kelly SAM, Summerbell CD, Brynes A. Whole-grain cereals for coronary
heart disease. Cochrane Database Syst Rev 2007; DOI:
10.1002/14651858.CD005051.pub2. Available at:
http://www.mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD00
5051/frame.html.

A cross-sectional analysis of a large healthcare provider
organization in Israel has revealed an association between psoriasis
and atherosclerosis and psoriasis and diabetes mellitus.

Results of the study, by Dr. Jonathan Shapiro of the Maccabi Health
Services in Ramat Hasharon and colleagues, are published in the
April issue of the Journal of the American Academy of Dermatology.

The investigators included 46,095 patients with psoriasis and
1,579,037 patients without psoriasis in their analysis. The
proportion of patients with diabetes was significantly higher among
those with psoriasis than controls, with an odds ratio of 1.27.

The same was true of atherosclerosis and psoriasis, with an odds
ratio of 1.28.

Dr. Shapiro's team analyzed the effect of various risk factors among
the psoriasis patients and found a link between diabetes and the use
of potent topical steroids as well the use of methotrexate,
cyclosporine and acitretin.

They also found a link between the use of phototherapy and
atherosclerosis.

The investigators acknowledge that the study design may contain
information and selection bias.

In addition, the database contains computerized information from
only 1997 forward, and does not include the date of disease onset.
Therefore, implications on causality cannot be made.

Despite these limitations, Dr. Shapiro's team said the associations
found could have "major public health issues and should be addressed
in the management of all patients with psoriasis."

J Am Acad Dermatol 2007;56:629-634.

The overall prevalence of type 2 diabetes has increased 5-fold in
the United States since the 1960s, and children and adolescents are
among those affected. However, children often exhibit no symptoms;
physicians therefore need to be alert for this disease in children
and open to the possibility that patients in their 20s might be
suffering from the long-term complications of preexisting type 2
disease, according to speakers here at the annual meeting and
clinical congress of the American Association of Clinical
Endocrinologists.

Although many children are at risk for type 2 diabetes,
currently "we have rather poor information on its prevalence in the
United States," said Peter H. Bennett, MB, from the Phoenix,
Arizona, research branch of the National Institute of Diabetes and
Digestive and Kidney Diseases (NIDDK) of the National Institutes of
Health. Scientists first identified type 2 (formerly "adult onset")
diabetes among the Pima Indians in the mid-1960s. In a recent
survey, approximately 20% of the diabetes diagnosed by physicians in
Pima Indians younger than 20 years was type 2. "We'll have more
definitive information fairly shortly" about national prevalence,
Dr. Bennett told the audience.

"One of the difficulties ¡X still ¡X is in making the clinical
decision of whether a child has type 1 or type 2 diabetes," Dr.
Bennett explained. There are several characteristics that
differentiate the two. Dr. Bennett reported that among the Pima, 92%
of children with type 2 diabetes also had a family history of type 2
disease, most often in the mother. Other features include obesity
(body mass index of 30 kg/m2 or greater), (68%), being asymptomatic
(78%), and ketoacidosis (about 10%). These children and adolescents
are not insulin-dependent and may stay that way for years, he said.
They are also glutamic acid decarboxylase (GAD) antibody¡V and islet
cell antibody (ICA)¡Vnegative.

Acanthosis nigricans has received attention as a type 2 diabetes
sign, but Dr. Bennett noted that this dermatologic condition may
simply indicate increased insulin resistance. He emphasized that
children with type 1 diabetes do have symptoms, while those with
type 2 usually do not. Hispanic children, African-American children,
and those of Polynesian heritage also seem more vulnerable to
developing type 2 diabetes than white children, although obesity and
being female clearly increase the risk in all ethnic groups, he
said. Currently, there is no direct evidence that physical
inactivity, separate from its effect on body mass index, is a risk
factor for type 2 diabetes in youngsters.

Surprisingly, "breast-feeding is protective" against type 2
diabetes, Dr. Bennett said. Pima Indian children who are breast-fed
for at least 2 months are 40% less likely to develop the disease,
and this protective effect has been confirmed by studies among
Aboriginal Canadians. There also appears to be a dose-response
relationship, with more protection conferred to children who were
breast-fed longer. In an interview with Medscape, Dr. Bennett said
that another supportive study involving about 1000 subjects will be
presented at the American Diabetes Association 67th Scientific
Sessions in June this year. Breast-feeding causes "a marked decrease
in diabetes in all populations so far studied," he said.

Paul S. Jellinger, MD, from the Center for Diabetes and Endocrine
Care at the University of Miami School of Medicine in Hollywood,
Florida, moderated this session. He told Medscape that "[I]nternists
and endocrinologists will be seeing individuals in their 20s and 30s
with the complications of diabetes, because diabetes was present
from age 12 or 13 on.

"They need to think about the vascular and renal complications of
this disease. Most of them are sort of aware, but they need to
realize that not all diabetes [in children] is type 1, and for a
growing number, it is type 2," Dr. Jellinger said.

This work did not receive commercial support (it received government
funding). The speaker reports no relevant financial relationships.

AACE 16th Annual Meeting and Clinical Congress: General Session.
Presented April 14, 2007.

Simple hypercholesterolemia is different from combined
hyperlipidemia, which is associated with obesity and metabolic
syndrome, and the two conditions respond somewhat differently to
different degrees of dietary fat modification and restriction. But
based on a review of the research to date, restricting total fat
intake to less than 25% of calories "doesn't serve anybody well,"
Robert H. Knopp, MD, professor of medicine at the University of
Washington in Seattle, told Medscape. He presented his findings here
at the annual meeting and clinical congress of the American
Association of Clinical Endocrinologists.

Combined hyperlipidemia is defined as increased low-density
lipoprotein (LDL) cholesterol, decreased high-density lipoprotein
(HDL) cholesterol, and increased triglyceride levels.

The National Cholesterol Education Program (NCEP) ATP III Guidelines
currently advocate a fat intake of 25% to 35% of total calories. In
ongoing work, Dr. Knopp is studying the efficacy of a diet that is
40% fat in people with combined hyperlipidemia. "A higher-fat diet
for obese people might be better," he said. But for lean people with
simple hypercholesterolemia, dietary management alone might be
effective.

Dr. Knopp also presented his findings from a recent pilot study in
20 subjects with simple hypercholesterolemia; 10 subjects received
ezetimibe plus coleseveiam hydrochloride, while 10 received
ezetimibe alone (Metabolism. Dec 2006;55(12):1697-1703). After 12
weeks, no difference was observed between the two groups. Dr. Knopp
told Medscape that he was surprised by his findings. "I thought the
combination would be better than one alone," he said.

Extremely low fat diets fail to show a benefit because below a
certain threshold, the body will manufacture its own saturated fat,
Dr. Knopp explained. He described both published and unpublished
research.

The diet-heart hypothesis was tested early in the Finnish Mental
Hospital Study, a well-controlled, 12-year comparison published in
The Lancet in1972 (Oct 21, 1972;2(7782):835-838). The researchers
substituted skim milk and soy for saturated fats in these captive
subjects, and observed "a major lowering in cholesterol" of about 30
mg/dL, and heart disease incidence dropped by one-half to two-
thirds, Dr. Knopp said. But early attempts to replicate
this "Mediterranean diet" by the National Cancer Institute were
stalled by methodological hurdles. "So the idea of substituting
polyunsaturated fats for saturated fats went out the window, at
least in the United States," Dr. Knopp said.

Instead, replacing fat with carbohydrate became popular in the
1980s. But Dr. Knopp cited studies showing that high carbohydrate
diets raise triglyceride levels and fail to show any weight-loss
advantage. Animal studies suggest that when dietary fat intake falls
below 25% of total calories, the liver compensates by lipid
hypersecretion. "The main message here is that the typical low-fat
diet does not appear effective in combined hyperlipidemia," Dr.
Knopp said.

The high-fat, Atkins-type diet is similarly ineffective, Dr. Knopp
said. This diet tends to increase LDL cholesterol, even when people
are actively losing weight. He added that researchers have yet to
report on this diet's cardiovascular outcomes.

"This is someone who has enormous historical knowledge in this
field, which is terribly important because managing lipids and their
effects on health is a long-term study," Yank Coble, MD,
distinguished professor and director of the Center for Global Health
and Medical Diplomacy at the University of North Florida in
Jacksonville, and moderator of the session, told Medscape. He noted
that negative studies often fail to get published, and that
regrettably, diet strategies become popular among the public even
with "no substance" behind them.

Dr. Coble said that physicians should take into account the
individual nature of these conditions and should emphasize moderate
diet and aerobic exercise for patients with combined hyperlipidemia.
He also said he found Dr. Knopp's research on ezetimibe and
colesevelam HCl "pretty convincing," and that a one-drug approach is
likely to have fewer adverse effects than a combination therapy.

The study was independently funded. The authors report no relevant
financial relationships.

AACE 16th Annual Meeting and Clinical Congress: General Session.
Presented April 15, 2007.

With hopes of making the medical therapy of chronic heart failure
less of an art and more of a science, the natriuretic peptides are
under scrutiny as possible targets for medical therapy in the
outpatient setting. A randomized trial, one of several exploring the
issue and among the first to make it into print, suggested that the
biomarker-guided approach as a complement to traditional clinically
driven management led to greater use of evidence-based medications
and fewer clinical events [1].

Clinicians in the Systolic Heart Failure Treatment Supported by BNP
(STARS-BNP) trial prescribed more diuretics and especially ACE
inhibitors and beta blockers when they aimed dosage adjustments at
the achievement of plasma brain-type natriuretic peptide (BNP)
levels of <100 pg/mL, compared with guidance solely by clinical
signs and symptoms. The BNP-guided strategy was also associated with
a significant drop in the rate of the primary end point, HF-related
death or hospitalization.

The benefits observed in the study using the BNP-guided
approach "might actually be larger in routine clinical practice,"
according to the authors, Dr Patrick Jourdain (Hospitalier de René
Dubos, Pontoise, France) and colleagues. The patients' care was led
by HF specialists at dedicated heart-failure clinics, and at
baseline all were on furosemide and virtually all were on beta
blockers and either ACE inhibitors or angiotensin-receptor blockers
(ARBs) at recommended dosage levels, they observe.

The STARS-BNP publication was published online March 30, 2007 in the
Journal of the American College of Cardiology.

BNP on the frontier of HF management

"Identifying useful strategies to facilitate HF monitoring is a very
high priority in the heart-failure world, as the availability of
multiple effective therapeutic interventions now creates a need
for 'guides' that will let us know when patients are adequately
treated," observes Dr Clyde W Yancy (Baylor University Medical
Center, Dallas, TX), who wasn't involved in STARS-BNP. Methods under
exploration, he told heartwire, include biomarkers like the
natriuretic peptides, automated daily-weight algorithms, remote HF-
status monitoring systems, and implantable hemodynamic
monitors. "Nothing to date has been definitively demonstrated to be
truly superior to clinical judgment."

There is much evidence supporting levels of BNP as a risk stratifier
in the setting of acute MI and hospitalization for acute
decompensated HF, Yancy observed, "However, the unanswered question
is whether or not targeting a lowered BNP level via medical, device,
or surgical management will lead to better outcomes."

STARS-BNP randomized 220 patients in NYHA functional class 2-3 with
an LVEF <45% to one of the two outpatient management strategies, BNP-
guidance as a supplement to clinical judgment vs the traditional
approach on its own. During the first three months, medical therapy
was adjusted 134 times among the 110 patients in the BNP-guidance
group--specifically in pursuit of the BNP target on about 80% of
occasions; medications were changed 66 times among the 110
clinically managed patients (p<0.05). In both groups, about 40% of
the changes were to the diuretic dosage. But ACE-inhibitor/ARB and
beta-blocker use increased more in the BNP-guidance group.

The plasma-level target was somewhat elusive in the BNP-guidance
group; mean concentrations went from 352 pg/mL at baseline to 284
pg/mL after three months (p=0.03), and the proportion reaching the
target went from 16% to 33% (p=0.04).

Still, patients on BNP-guided management showed a significant
decrease in the primary end point of death or unplanned
hospitalization due to heart failure, fewer HF-related
hospitalizations, and better event-free survival. There were no
significant differences in all-cause mortality or all-cause
hospitalization.

STARS-BNP is among the first of a number of trials exploring whether
natriuretic-peptide-guided outpatient management can be a both
effective and practical strategy. It was associated with fewer CV
events, including hospitalization, in a pioneering trial with fewer
than 70 patients published in 2000 [2]. Others that are ongoing or
in the works have vivid acronyms like ESCAPE, TIME-CHF, RABBIT, and
BATTLESCARRED [3,4].

STARS-BNP in context

Another of the trials, presented in preliminary form at the American
Heart Association 2006 Scientific Sessions but as yet unpublished,
is the pilot study STARBRITE [5]. As reported by Dr Monica R Shah
(Washington Hospital Center, Washington, DC), the 130-patient trial
found no significant difference over three months between BNP-guided
and solely clinically based management in the primary end point
of "nonhospital days alive."

Compared with STARS-BNP, however, STARBRITE entered an arguably
sicker group of patients. They started out in NYHA class 3-4 and
with an LVEF <35% and had been randomized prior to discharge
following hospitalization for acute decompensation. Also different
was the study's BNP target for medical therapy, which was
maintenance at less than twice the BNP concentration at hospital
discharge.

Similar to STARS-BNP, STARBRITE saw significantly increased ACE-
inhibitor use (p=0.03) and a trend toward greater use of beta
blockers (p=0.08) in the BNP-guidance group.

Yancy called STARS-BNP "provocative" but in need of verification by
larger trials that account for the full range of available treatment
options for heart failure. The findings, he said, "would suggest
that BNP-guided therapy has some advantages over clinical
assessment, but there are important caveats. These data are likely
to be very center-specific and, as the authors point out, very much
patient-specific. We don't know how the findings would be altered
with a larger patient population, with a more diverse population,
and especially with the use of evidence-based device therapy."

STARS-BNP was funded by Biosite, for which Yancy reports he is a
consultant.

Jourdain P, Jondeau G, Funck F, et al. Plasma brain natriuretic
peptide-guided therapy to improve outcome in heart failure: The
STARS-BNP multicenter study. J Am Coll Cardiol 2007; 49:1733-1739.
Troughton RW, Frampton CM, Yandle TG, et al. Treatment of heart
failure guided by plasma amino-terminal brain natriuretic peptide (N-
BNP) concentrations. Lancet 2000; 355:1126-30.
Lainchbury JG, Troughton RW, Frampton CM, et al. NTproBNP-guided
drug treatment for chronic heart failure: design and methods in
the "BATTLESCARRED" trial. Eur J Heart Fail 2006; 8:532-8.
Brunner-La Rocca HP, Buser PT, Schindler R, et al. Management of
elderly patients with congestive heart failure---design of the Trial
of Intensified versus standard Medical therapy in Elderly patients
with Congestive Heart Failure (TIME-CHF). Am Heart J 2006; 151:949-
55.
Shah MR, Califf RM, Nohria A, et al. STARBRITE: A randomized pilot
trial of BNP-guided therapy in patients with advanced heart failure.
American Heart Association Scientific Sessions 2006; November 13,
2007; Chicago, IL. Abstract 2554.

A bariatric surgery procedure used for treating severe obesity is
now being explored as a cure for type 2 diabetes mellitus in normal-
weight and moderately overweight patients with diabetes. Specific
recommendations for using surgery in these patients are expected to
appear this summer, according to a presentation here at the annual
meeting and clinical congress of the American Association of
Clinical Endocrinologists.

When used as a last resort for weight management, certain gastric
bypass procedures have been known to completely reverse, or at least
mitigate, type 2 diabetes. Until recently, researchers had assumed
that weight loss alone was somehow responsible for this benefit.
However, new research in rodents and very preliminary work in humans
suggest that hormonal and metabolic changes caused by the surgery
must be responsible, not simple weight loss, said Karen Foster-
Schubert, MD, acting instructor at the University of Washington in
Seattle.

"We really don't know what is being affected yet," Dr. Foster-
Schubert told Medscape about the mechanism of diabetes reversal.
Research in the laboratory of her colleague, David E. Cummings, MD,
of the University of Washington, shows that ghrelin, a recently
discovered peptide that stimulates appetite, is decreased after
gastric bypass surgery. Other peptides, including the distal small
intestine hormone peptide YY (PYY), and glucagon-like peptide 1 (GLP-
1), secreted by intestinal L cells, increase after the operation,
she said.

Dr. Foster-Schubert reported on bypass operations performed on 2
mildly overweight patients under the care of Francesco Rubin, MD, of
the Institut de Recherche contre les Cancers de l'Appareil Digestif
(IRCAD) in Strasbourg, France, and the Catholic University of Rome,
Italy, and discussed at the International Conference on
Gastrointestinal Surgery to Treat Type 2 Diabetes (the "Diabetes
Surgery Summit") held in Rome, March 29-31, 2007. The data showed
that duodenal bypass dramatically lowered fasting glucose, fasting
insulin, and hemoglobin A1c levels in these 2 patients within 1
month after surgery. Yet the body mass indexes (BMIs) of these
patients have remained stable during 9 months of observation. One
patient has had a stable BMI of approximately 27 kg/m2, while the
other patient's BMI has ranged from 29 to 30 kg/m2. (A normal-weight
BMI is defined as 18.5 to 24.9 kg/m2; overweight is 25 to 29.9
kg/m2; and obesity starts at 30 kg/m2, with "super super obesity"
starting at 60 kg/m2.)

The surgical technique discussed by Dr. Foster-Schubert, Roux-en-Y
gastric bypass (RYGB), is one of several procedures indicated for
weight reduction. A recent meta-analysis of 22,094 patients showed
that 84% experienced complete reversal of type 2 diabetes mellitus,
with most stopping their oral medications or insulin injections
before leaving the hospital, Dr. Foster-Schubert said.

The ethics of using RYGB to treat a disease that can be managed
medically might be controversial, Dr. Foster-Schubert allowed. Those
who participated in the Diabetes Surgery Summit have announced that
they will publish recommendations for treatment by this summer, she
added.

Guidelines from the National Institutes of Health have set a BMI of
40 kg/m2 or greater as the threshold for bariatric surgery,
according to Jeffrey I. Mechanick, MD, associate clinical professor
of medicine at Mount Sinai Medical Center in New York City. The
surgery can cause a variety of complications, including electrolyte
abnormalities, nutrient deficiencies, kidney stones, and
osteoporosis, he said.

"There is an interest among bariatric surgeons in doing [surgery for
diabetes]," said Dr. Mechanick during an informal discussion with
reporters. "This is going to become an issue between the
endocrinologists and the surgeons." He added, "There's an economic
incentive. With more and more drugs, there will be less need for
bariatric surgery and a greater need for metabolic surgery and
diabetes surgery."

Drs. Foster-Schubert and Mechanick both expect many patients with
type 2 diabetes to want this surgery, despite its inherent risks,
including the risk of death. "It's a lot of heartache and headache"
to have diabetes, Dr. Foster-Schubert told Medscape. "I expect a
pretty large percentage of individuals would be interested, at least
in exploring the risks and benefits."

This research was independently funded. The authors report no
relevant financial relationships.

AACE 16th Annual Meeting and Clinical Congress: General Session.
Presented April 12, 2007.

Not all cardiac resynchronization therapy (CRT) is the same, and the
modes that involve biventricular (BiV) pacing may be the best, at
least when it comes to ventricular structural improvements. A
randomized comparison in patients with heart failure and ECG-defined
ventricular dyssynchrony found that simultaneous and sequential BiV
pacing both improved LV dimensions better than LV-only pacing [1].

The findings, based on the echocardiographic end points of a trial
called Device Evaluation of CONTAK RENEWAL 2 and EASYTRAK 2:
Assessment of Safety and Effectiveness in Heart Failure (DECREASE-
HF), were published online April 9, 2007 in Circulation.

According to the authors, Dr Rajni K Rao (University of California,
San Francisco) and associates, yet-unpublished results for the
trial's composite primary end point of peak VO2 and LV end-systolic
dimensions reflect the echo outcomes, in that improvements from LV
pacing fell behind those from either BiV mode.

The group randomized 306 patients with an LVEF <35% and QRS duration
>150 ms to CRT using one of the three pacing modes; only seven were
in NYHA class 4, the remainder were in class 3. Patients had to be
stable and on consistent dosages of both an ACE inhibitor and a beta
blocker for at least a month. The groups' mean LVEFs at entry were
similar; the overall average was 28%.

After six months:

• All three groups showed significant reductions in mean LV end-
diastolic and end-systolic dimensions and LV end-systolic volume
(LVESV).

• The two BiV modes, but not LV pacing, were associated with
significant reductions in LV end-diastolic volume.

• Significantly more patients in the simultaneous-BiV group (40%)
showed a >25% reduction in LVESV compared with the sequential BiV
and LV pacing groups (42% and 20%, respectively; both p=0.001 vs
simultaneous BiV).

The groups showed significant and similar increases in LVEF over six
months--the overall mean improvement was by 6.7 absolute percentage
points--but the LV pacing group was alone in not showing
significantly improved mitral-valve function.

In clinical practice, observed Rao et al, the pacing mode and, in
sequential BiV pacing, VV timing, can be tailored to individual
patients based on their acute hemodynamic responses; that it wasn't
done in their trial, they write, could have influenced the results.

DECREASE-HF was funded by Boston Scientific, from which Rao and
coauthors Dr David De Lurgio (Emory University, Atlanta, GA) and Dr
Elyse Foster (UCSF) report receiving research grants and of which
coauthor Jill Schafer is an employee.

Rao RK, Kumar UN, Schafer J, et al. Reduced ventricular volumes and
improved systolic function with cardiac resynchronization therapy. A
randomized trial comparing simultaneous biventricular pacing,
sequential biventricular pacing, and left ventricular pacing.
Circulation 2007: DOI:10.1161/CIRCULATIONAHA.106.634444. Available
at: http://circ.ahajournals.org.

A new type of iodine-based contrast agent that interacts with
activated macrophages may one day be used in humans during
multislice computed tomography to identify plaques at risk of
disruption and thrombus formation [1]. In a study published online
April 8, 2007 in Nature Medicine, Dr Fabien Hyafil (Mount Sinai
School of Medicine, New York, NY) and colleagues tested the contrast
agent in rabbits and say the in vivo detection of macrophages could
lead to improved diagnosis and prognosis, not only in
atherosclerosis but also in other diseases.

"The thought was to inject a contrast agent during CT, like we do
when we do lumen imaging, but let's have that contrast agent be more
specific, with properties that would let it interact with the vessel
wall and target important cells or important plaque components,"
senior author on the study, Dr Zahi A Fayad (Mount Sinai School of
Medicine), explained. "And one of the more important components of
plaque is inflammation: we know that plaques that have a lot of
macrophages in them are basically unstable plaques; that's widely
accepted."

Commenting on the study for heartwire, Dr Deepak Bhatt (Cleveland
Clinic, OH) called the concept "intriguing."

"If this technique or some related technique pans out, it could
really change the way that we practice cardiology," Bhatt said. "We
could really be preventive cardiologists."

The quest for the vulnerable plaque

The ability to noninvasively screen for high-risk, or "vulnerable,"
plaques is one of cardiology's holy grails. Fayad reminded heartwire
that existing noninvasive imaging technologies are doing a better
and better job of imaging the coronary lumen and identifying
stenoses, but they cannot characterize the vessel wall. While MRI
has shown promise for plaque characterization, the technology is
still limited by respiratory and cardiac motion. In CT, the iodine
contrast solution that is used can help identify stenoses, but it
does not interact with the vessel wall, he said.

For their study, Fayad, Hyafil, and colleagues used an iodinated
nanoparticulate contrast agent called N1177 (Nanoscan Imaging,
Lansdale, PA). First, they tested the uptake of N1177 by mice
macrophages in vitro, reporting that dark granules could be seen in
the cytoplasm of macrophages incubated with N1177, but not in
macrophages incubated with conventional CT contrast agent.

Next, investigators injected the N1177 contrast agent into
nonatherosclerotic rabbits and evaluated its kinetics and
distribution in the blood and macrophage-rich tissues, using serial
CT imaging. This time, organs known to contain macrophages such as
the liver and spleen were found to contain higher amounts of N1177,
as evidenced by greater CT enhancement, than those same organs prior
to contrast injection or following standard contrast dye injection.

Finally, using a model of atherosclerotic disease involving balloon
injury to the aortas of hypercholesterolemic rabbits, investigators
report that enhancement of atherosclerotic plaque in rabbit aortas,
as seen on CT, was greater after injection of N1177 than after
standard CT contrast dye. No such enhancement was seen in
nonatherosclerotic rabbits after injection of either contrast agent.
Subsequent pathological studies showed that N1177 uptake was indeed
highest in aortic sections with the highest distribution of
macrophages.

Honing in on high-risk plaque

"The main purpose of this study was to do a very thorough
characterization to figure out where these particles are landing--
are they really landing in the macrophages or not," Fayad said. "In
this study, we demonstrated that we can look directly at macrophages
with CT, which is the ultimate, noninvasive coronary imaging system
today."

According to Bhatt, the future of such an agent and technique is
based on several premises, starting with the assumption that
macrophage-rich plaques are indeed high-risk plaques. "We don't
really know for sure if these plaques are definitely the ones that
are killing people," Bhatt said. "The only way to know that for sure
would be to use this technology in humans, and assuming that it's
not toxic and that there are no safety issues, identify those with
vulnerable plaques based on this test and see if those folks do go
on to have more heart attacks, strokes, and deaths. The next step
would be to prove that that information is clinically useful. That
is, you've identified a patient with vulnerable plaques--now, can
you do an intervention to modify that risk? And once that is done,
assuming it could be done, then the picture is complete."

He continued: "There are a lot of steps there between the basic
science and the therapeutics, but I think the logic is sound."

Bhatt also pointed out that the use of a noninvasive screening test
using CT is extremely attractive compared with other, invasive
methods for characterizing plaques, such as IVUS or optical
coherence tomography.

"If you take the 50 million people who are at moderate risk for
atherosclerotic disease in the US and do an invasive procedure on
them, that would break the bank, and beyond that, there is always
going to be some degree of risk with an invasive procedure. That's
not practical. . . . Of the different technologies I've seen--with
the caveat that this study is really early and in an animal model--
it just seems extremely promising."

The study authors note that, should the agent work in humans, it
might eventually be possible to couple the diagnostic agent with
some kind of therapeutic agent that could specifically target
macrophages in various disease states, not just atherosclerosis, but
also infectious and autoimmune diseases where macrophages play a
role.

"That's Star-Trek-type thinking," Bhatt acknowledged, "but I think a
lot of doctors are Star Trek fans. In the back of our minds, we're
all thinking it should be possible to get there. This study really
did excite me because it's really a first step toward Star-Trek-type
therapy.

Hyafil F, Cornily JC, Feig JE, et al. Noninvasive detection of
macrophages using a nanoparticulate contrast agent for computed
tomography. Nat Med 2007; DOI:10.1038/nm1571. Available at:
http://www.nature.com/nm/index.html.

New animal data published this week point to a previously
unsuspected link between the immune system and the regulation of
lipid levels and may help to explain how chronic inflammation is
associated with hyperlipidemia [1]. Investigators from the
University of Chicago discovered an interaction between T cells and
liver cells that appears to regulate lipoprotein homeostasis, a
process mediated by ligands in the tumor necrosis factor superfamily.

"The role of inflammation, per se, on hyperlipidemia has not been
well understood," Dr Godfrey Getz (University of Chicago, IL), one
of the study investigators, told heartwire. "We show that some of
the inflammatory cells may indeed regulate lipid metabolism. People
with chronic inflammatory disease, such as lupus and rheumatoid
arthritis, often have hyperlipidemia and are at increased risk of
cardiovascular disease. The mechanism we have shown may help to
explain this effect of these diseases on blood lipids."

The investigators, led by Dr James Lo (University of Chicago, IL),
say the link between the hepatic T cells in lipid metabolism is
surprising, although they have long observed that experimental
immune-deficient animals have lower blood lipid levels than animals
with normal immune systems.

The study is published in the April 13, 2007 issue of Science.

LT and LIGHT are proinflammatory ligands

The researchers specifically turned their attention to the effects
of lymphotoxin (LT) and LIGHT. These are two potent proinflammatory
ligands, expressed primarily on T cells, both of which bind to the
lymphotoxin {:beta:} receptor (LT{:beta:}R), a member of the tumor
necrosis factor family. Previous disruptions of LT{:beta:}R
signaling in mice have been shown to result in different phenotypes,
including lymph node aplasia, autoimmunity, viral infection, and
impaired immunoglobin responses, the authors note.

In a mouse model, dysregulation of LIGHT expression on T cells
resulted in hypercholesterolemia and hypertriglyceridemia. When T
cells expressing LIGHT were introduced into mice fed a regular and a
high-fat diet, lipid levels increased. In LDL-receptor-deficient
mice, which lack the ability to control lipid levels in the blood,
inhibiting LT and LIGHT signaling with a soluble LT{:beta:}R decoy
protein attenuated the dyslipidemia.

"LIGHT particularly, and perhaps LT, expressed in T cells play a
role in the regulation of plasma cholesterol," said Getz. "This is
at least in part the result of an interaction of T cells with the
major liver cells, hepatocytes. The T cell subset, natural killer T
cells, seems to be a major actor in this."

The researchers then examined levels of hepatic lipase, an enzyme
made in the liver and secreted into the blood, where it plays a role
in lipid metabolism. Mice with T cells expressing LIGHT manufactured
and secreted less hepatic lipase and had higher plasma lipid levels.

"In the presence of LIGHT, [hepatic lipase], which is required for
the full competence of the animal to remove lipids from the blood,
is substantially downregulated," Getz told heartwire. "There is
evidence in the literature that hepatic lipase gene variations are
risk factors for cardiovascular disease in humans."

Next steps, say investigators, are to determine whether the immune
response can be manipulated to have a positive impact on lipid
metabolism. The group is now focusing on the effects of these
manipulations on atherosclerosis, although Getz cautions that that
the outcomes are not always as predicted.

Lo JC, Wang, Tumanov AV, et al. Lymphotoxin {:beta:} receptor-
dependent control of lipid homeostasis. Science 2007; 316:285-288.

A lack of health insurance among US residents is associated with
increased rates of stroke and death, a new study shows.

Investigators found that individuals without health insurance are
much more likely to forgo routine physical examinations and are less
likely to be aware they have high blood pressure, diabetes, or
hypercholesterolemia.

Interestingly, however, while a lack of health insurance was linked
to an increased stroke risk, the same did not hold true for
myocardial infarction (MI) risk.

"We speculate that this may relate to the relative importance of
hypertension as a risk factor for stroke," the study's principal
investigator, Angela Fowler-Brown, MD, from Beth Israel Deaconess
Medical Center, in Boston, Massachusetts, said in a statement.

"Hypertension is the most powerful risk factor for stroke, and in
our study we found that hypertension was significantly less likely
to be well-controlled in those lacking insurance.

"While hypertension is also an important risk factor for myocardial
infarction, other factors such as inflammation, cholesterol, and
inherited traits may be of greater relative importance in the
development of MI than in stroke," she added.

The study is published in the April issue of the Journal of General
Internal Medicine.

Uninsured Have More CVD Risk Factors

Using data from 15,792 participants enrolled in the Atherosclerosis
Risk in Communities, a longitudinal epidemiologic study,
investigators estimated the hazard of MI, stroke, and death
associated with insurance status.

At study entry, participants were 45 to 64 years old and were
enrolled between 1987 and 1989. Data on cardiovascular risk factors,
personal medical histories, socioeconomic status, and family history
were collected at baseline. In addition, all study participants
underwent physical examination and cardiovascular and laboratory
testing. Patients were also asked about their insurance status.

Individuals were then reevaluated using the same tests every 3 years
for a total of 4 visits. In addition, annual telephone surveys
assessed changes in health status.

The study's primary outcomes included incident MI, stroke, and all-
cause mortality. Frequency of routine physical examinations,
awareness of a personal diagnosis of cardiovascular risk factors,
and adequate control of cardiovascular risk factors were secondary
study end points.

Compared with insured individuals, subjects who reported being
uninsured at least once were more likely to be female and nonwhite,
with lower education levels and family income.

Uninsured individuals were also more likely to have cardiovascular
risk factors, diabetes, hypertension, and higher body mass index and
be current smokers.

Number of Uninsured "Alarming"

Within the total study group there were 444 strokes, 968 MIs, and
1,157 deaths. After adjustment for baseline characteristics, a lack
of insurance was associated with an increased risk for stroke and
all-cause death compared with those who had health insurance.

In addition, the authors report, individuals who were not insured
were less likely to undergo routine physical examinations and had a
higher adjusted risk of being unaware of a personal diagnosis of
hypertension or hyperlipidemia compared with their insured
counterparts.

According to the authors, the number of US residents without health
coverage is "alarming." According to 2005 estimates, 46.6 million US
residents, or 15.9% of the population, are without health insurance
coverage.

"We believe our findings underscore the great importance of medical
insurance in maintaining the health of the population. As medical
science continues to advance, we fear that the health disparities
between those who have access to medical care through insurance and
those who do not may continue to grow," said Dr. Fowler-Brown.

J Gen Intern Med. 2007;22:502¡V507.

Different ethnic groups develop clinically significant increases in
lipid, glucose, or blood-pressure levels at much lower body-mass
indexes (BMIs) than those predicted in established BMI cut points,
new research shows [1]. The study is the latest to question the
validity of BMI--developed and validated in people of European
descent--as a tool for risk stratification in people from other
ethnic backgrounds.

Fahad Razak (McMaster University, Hamilton, ON) and colleagues
publish their findings online April 9, 2007 in Circulation.

According to study coauthor Dr Sonia S Anand (McMaster University),
the analysis was prompted by the observation that certain ethnic
groups, including South Asians and aboriginal people, have an
increased prevalence of diabetes at much lower BMIs than do people
of European descent.

BMI cut points may not be SHAREd

Razak, Anand, and colleagues analyzed data for 1247 patients,
collected in the Study of Health Assessment and Risk in Ethnic
Groups (SHARE) and in aboriginal peoples (SHARE-AP), verifying
ethnicity from study participants. Subjects underwent tests for
glucose, lipids, waist and hip ratio, and BMI; 169 patients were
excluded for having established diabetes.

In the remainder, researchers report a "marked ethnic variation" in
BMI, with aboriginals having mean BMIs that were more than 7 kg/m2
greater than the Chinese participants, with South Asians and
Europeans distributed in between. Glucose levels were significantly
higher in aboriginals and South Asians, with South Asians also
having the worst lipid profiles, while Chinese subjects had higher
blood-pressure levels than Europeans. In a factor analysis, using
the parameters of glucose, lipid, and blood pressure, the authors
determined the cut point at which nonwhite ethnic groups developed
abnormalities in these parameters. The cut point for all three
parameters in Europeans was a BMI of 30, the BMI that is also the
accepted cut point for obesity. Strikingly, however, cut points in
the three other groups were much lower.

"Compared with a BMI in the 30s for European whites, the South
Asian, aboriginal, and Chinese individuals started to show
abnormalities in their glucose parameters above a BMI of 21, which
is far lower than 30," Anand said, adding that each point on the
standard BMI scale is equivalent to about six pounds.

"So if we say that's about a 54-pound difference, we're starting to
see changes at very low BMIs in the nonwhite groups compared with
the white group. We need to reevaluate our normal BMI ranges,
because the normal BMI is defined by a BMI of 25, but if we use that
as 'normal' in someone of South Asian origin, they in fact might be
about 25 pounds overweight, and that's why we see a large number of
nonwhite individuals already having diabetes despite having 'normal'
BMIs. . . . This calls for second look at cut points for BMI.¡¨

Other differences seen

Other surprising differences also emerged in the data, Anand pointed
out. While a low BMI was associated with clinically significant
glucose and lipid increases in South Asians, in the Chinese and
aboriginal groups, lipids didn't reach abnormal levels until BMIs
were in the 26-point range. For blood-pressure increases, only the
Chinese seemed to be at risk at lower BMIs. By contrast, aboriginal
people did not develop abnormal blood-pressure levels until BMIs hit
33. "We would have expected that aboriginal people would have had
some relationship between a lower BMI cut point and blood pressure,
but in fact they seem to be able to preserve a low blood pressure
despite having very high BMIs," Anand said.

Another recent analysis of the INTERHEART study participants, also
carried out by McMaster investigators, suggested that BMI be dropped
altogether as a risk-stratification tool, precisely because risk
stratification based on BMI values can be inaccurate and misleading
in different ethnic groups, as reported by heartwire. According to
Anand, she and her coinvestigators were unable to include waist
circumference or waist-to-hip ratios in the current analysis, but it
is something the group intends to look at within the SHARE/SHARE-AP
cohort.

"I would concur that data from the INTERHEART study clearly showed
it was the distribution of fat that's more important than body
weight per se," Anand said. "This raises the point that when
different groups around the world, like NHANES or public-health
agencies, are trying to put out recommendations for target BMI, they
probably should have different BMI targets for different ethnic
groups."

While there may be more quibbling about the precise cut points
needed for different groups, Anand believes the findings from the
current study are immediately relevant for clinicians.

"They need to consider screening people of South Asian, aboriginal,
or Chinese origin for problems like glucose and lipids at lower
BMIs," she said. "So if a South Asian patient presents with a BMI of
25, physicians shouldn't assume that their blood sugar will be
normal. They should be aware that that's actually overweight for a
South Asian and screen him or her for glucose and lipid problems."

Razak F, Anand SS, Shannon H, et al. Defining obesity cut points in
a multiethnic population. Circulation 2007; DOI:
10.1161/CIRCULATIONAHA.106.635011. Available at:
http://circ.ahajournals.org.

Vildagliptin, a new dipeptidyl peptidase-4 inhibitor, is a useful
therapeutic option in patients with type 2 diabetes inadequately
controlled with metformin monotherapy, researchers report in the
April issue of Diabetes Care.

"Vildagliptin can be used successfully alone or in combination with
metformin," Dr. Alan J. Garber told Reuters Health. "When used in
combination, the effects are additive and get many more patients to
the glycemic goals required to minimize complications of diabetes."

Dr. Garber, of Baylor College of Medicine, Houston, Texas, and
colleagues note that although metformin is the most commonly
prescribed first-line antidiabetes drug worldwide, due to the
natural progressive worsening of blood glucose control, combination
therapy usually becomes necessary.

To investigate whether vildagliptin might be helpful under these
circumstances, the researchers studied 544 patients. In addition to
continuing their metformin regimen, they were randomized to receive
vildagliptin 50 or 100 mg per day or placebo.

At the end of the 24-week study, compared to placebo, there was an
adjusted mean 0.7% reduction in HbA1C in the 50 mg group and a 1.1%
reduction in the 100 mg group.

There was also a significant improvement in fasting plasma glucose.
This amounted to a 0.8 mmol/L reduction in the 50 mg group and 1.7
nmol/L reduction in the 100 mmol/L group. The incidence of adverse
events was similar across groups.

"In view of its efficacy and excellent tolerability profile,
vildagliptin may be a useful addition to the therapeutic
armamentarium for treatment of patients with type 2 diabetes," the
researchers conclude.

Diabetes Care 2007;30:890-893