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Newswise — April 11 2012 – Although observational studies have suggested that losartan, a drug used primarily for the treatment of hypertension, may be associated with an increased risk of death among patients with heart failure compared with other medications in the same class of drugs (angiotensin II receptor blockers [ARBs]), an analysis that included nearly 6,500 patients found that overall, use of losartan was not associated with increased all-cause death or cardiovascular death compared with use of the ARB candesartan, according to a study in the April 11 issue of JAMA.

Henrik Svanstrom, M.Sc., of Statens Serum Institut, Copenhagen, Denmark, and colleagues conducted a study to assess whether use of losartan is associated with increased all-cause mortality in heart failure patients compared with candesartan. The study, which included data from a nationwide Danish registry, linked individual-level information on hospital contacts, filled prescriptions, and potential confounders (factors that can influence outcomes). Patients ages 45 years and older with first-time hospitalization for heart failure in 1998-2008 were identified from the registry. New users of losartan and candesartan were selected for inclusion in the study cohort. The final study group included 6,479 patients; 2,082 users of candesartan and 4,397 users of losartan.

During follow-up, there were 2,378 deaths in the study population. Among these, 330 occurred during ongoing candesartan use and 1,212 during ongoing losartan use. The researchers found no significantly increased risk of death associated with use of losartan as compared to candesartan. Also, use of losartan was not significantly associated with an increased risk of cardiovascular mortality compared with candesartan use.

The authors did find that use of low-dose losartan (12.5 mg) was associated with a more than 2-fold increased risk of mortality as compared with high doses of candesartan (16-32 mg). Treatment with 50 mg of losartan (medium dose) was also associated with a higher mortality risk. However, there was no increased risk associated with use of 100 mg of losartan (high-dose).

The authors write that compared with previous observational studies, “our data provide a more detailed insight into the complexity of the association between losartan use and mortality risk in heart failure.”

“This large, nationwide cohort study of patients with heart failure found no significantly increased risk of all-cause mortality associated with use of losartan as compared with candesartan. Whereas lower doses of losartan were associated with increased mortality risk as compared with higher doses of candesartan, there was a decreasing risk of mortality with increasing losartan dose; and no significantly increased mortality risk was observed when comparing the highest dose of losartan against the highest doses of candesartan. These findings do not support the hypothesis of differential effects of specific ARBs in patients with heart failure,” the researchers conclude.

Cardiology researchers at Thomas Jefferson University show therapeutic effectiveness and safety of ‘next great thing in heart failure’ for humans.

PHILADELPHIA—A promising gene therapy developed, in part, at Thomas Jefferson University’s Center for Translational Medicine to prevent and reverse congestive heart failure is on the verge of clinical trials, after years of proving itself highly effective in the lab and a large animal study.

Reporting in the online July 20 issue of Science Translational Medicine, cardiology researchers have demonstrated feasibility, the long-term therapeutic effectiveness and the safety of S100A1 gene therapy in a large animal model of heart failure under conditions approximating a clinical setting.

“This is the last step you have to take to finish a very long line of research,” said Patrick Most, M.D., adjunct assistant professor of medicine at Thomas Jefferson University, and lead author of the study who now heads the Institute for Molecular and Translational Cardiology at the University of Heidelberg, Germany. “The reversal of cardiac dysfunction in this pre-clinical heart failure model in the pig by restoring S100A1 levels in practically the same setting as in a patient is remarkable and will pave the way for a clinical trial.”

The therapy works by raising diminished levels of the protein S100A1, a calcium-sensing protein in the diseased heart muscle cell, to normal. Previous research suggests this will prevent against heart failure development, particularly in people who have had a heart attack.

According to Dr. Most, “the therapeutic profile of S100A1 is a unique one as it targets and reverses the underlying causes of heart failure: progressive deterioration of contractile performance, electrical instability and energy deprivation.”

About six million people in the United States have heart failure, and it results in about 300,000 deaths each year.

Work on S100A1 started bench side 15 years ago with Dr. Most and Walter J Koch, Ph.D., now director of the Center for Translational Medicine in the Department of Medicine in Jefferson Medical College of Thomas Jefferson University, who, with his team, have moved the research closer to bedside ever since.

Five years ago, Jefferson researchers showed that increasing levels of the protein above normal helped protect mouse hearts from further damage after simulated heart attacks. The hearts worked better and had stronger contractile force.

“We have pursued a completely different path over the years,” said Dr. Most. “We have set up a translational pipeline and don’t stick to just one model system. We took it step by step, and did whatever was necessary to go to the next level. We realized early on that a mouse is not a man. You need to design target-tailored translational research strategies and work in human-relevant model systems to take molecular discoveries from bench to bedside.

“With such a translational roadmap at hand, we are in the unique position to accelerate future development of molecular therapies.”

In their latest study in Science Translational Medicine, Drs. Koch and Most and their team of researchers used a pig model—this type more closely resembles human physiology, function and anatomy—to determine the effectiveness and safety of the S100A1 gene therapy. Researchers were also able to administer it with certified catheters and delivery routes, just as a human patient would receive it. “We’ve shown its effectiveness in the lab. It worked in mice and rats, then pigs and now it’s ready for humans,” Dr Most adds.

Heart failure was induced in the pigs, and at 14 weeks showed significantly decreased S100A1 levels. Treatment, however, with the gene therapy prevented and reversed development of heart failure by restoring the S100A1 protein levels or getting them above normal.

“This therapy gets to the core of the disease,” said Dr. Koch, who received the “Outstanding Investigator Award” for 2011 by the International Society for Heart Research for his work in heart failure gene therapy. “They are not just beta blockers or ancillary drugs, which only block the damage. This therapy makes the heart beats stronger and overcomes the damage from previous heart attacks. It’s the next great thing in heart failure.”

This is the final set of preclinical data needed to apply for investigational new drug status with the U.S. Food and Drug Administration and advance to a phase I clinical trial.

Researchers say one of the next steps is to find industry or private partners to help fund the work, as well as recruit eligible patients to enroll in the clinical trial.

“With National of Institutes of Health money in jeopardy, this could be translated faster with funds from other sources,” said Dr. Koch. “It could fund both ongoing research with other targets using our translational roadmap and to take this particular target for heart failure into humans.”

An inexpensive, routine blood test could hold the key to why some patients with congestive heart failure do well after being discharged from the hospital and why others risk relapse, costly readmission or death within a year, new Johns Hopkins research suggests.

In a study reported online by the American Journal of Cardiology, Henry J. Michtalik, M.D., M.P.H., and his colleagues tested heart failure patients on admission and discharge for levels of a protein that’s considered a marker for heart stress. In previous studies, the levels of this protein, N-terminal pro-B-type natriuretic peptide, or NT-proBNP, have been correlated with heart failure symptoms and have been associated with an increase in adverse outcomes.

They found that patients whose protein levels dropped by less than 50 percent over the course of their hospital stay were 57 percent more likely to be readmitted or die within a year than those whose levels dropped by a greater percentage.

Testing for NT-proBNP at the beginning and end of hospitalization, Michtalik says, could help doctors and hospitals make better decisions about which patients are truly ready to be released and which ones are at higher risk for relapse, readmission or worse. Typically, he adds, patients are already tested for this heart failure marker upon admission.

“These patients feel better. They look better. But this study suggests many of them may not be completely better,” says Michtalik, a research and clinical fellow in the Johns Hopkins University School of Medicine’s Division of General Internal Medicine. “Even though a doctor has determined the patient is ready to go home, a change in this biological marker of less than 50 percent means the patients are at much higher risk and would likely benefit from more intensive treatment, monitoring or outpatient follow up.”

Congestive heart failure occurs when the heart can’t pump enough blood to meet the demands of the body, resulting in heart enlargement and fluid swelling. It is most often caused by coronary artery disease, high blood pressure, heart valve disease and alcohol abuse. Roughly 5.7 million people in the United States have heart failure, which kills about 300,000 each year, and results in repeat hospitalizations for many patients. Readmission rates are a focus of efforts to reduce health care costs, Michtalik notes.

Michtalik and his colleagues studied 241 heart failure patients admitted to The Johns Hopkins Hospital between June 2006 and April 2007 who were treated with intravenous diuretics to remove fluid from the body.

Within the first 24 hours, blood was drawn from the patients and tested for NT-proBNP, and patients were treated for their symptoms by their individual doctors. Though the patients’ NT-proBNP levels were tested again at discharge, the decision for or against discharge was determined by clinical judgment alone and the treating physicians were not aware of the protein’s level at discharge.

Analysis showed that patients whose protein levels decreased by less than 50 percent over the course of the several days to a week that they were in the hospital were at the highest risk for readmission or death.

“Our research suggests that maybe clinical judgment isn’t enough to decide whether a heart failure patient is ready to be discharged,” he says. “These patients may benefit from being treated until the heart failure marker, NT-proBNP, decreases by a certain percentage, something that is not considered now.”

Michtalik says a good next step would be a prospective randomized trial that examines whether hospitalized heart failure patients do better when their doctors work intensively to decrease the heart failure marker over the course of their hospital stays.

Other Johns Hopkins researchers involved in this study include Hsin-Chieh Yeh, Ph.D.; Catherine Y. Campbell, M.D.; Nowreen Haq, M.D., M.P.H.; Haesong Park, M.D., M.P.H.; William Clarke, Ph.D., M.B.A.; and Daniel J. Brotman, M.D.

Implantable Sensor Lowers Hospitalization Rate for Heart Failure

The sensor detects changes in pulmonary artery pressure.

Heart failure patients admitted to general wards are twice as likely to die as those admitted to cardiology
wards, shows a national audit of the treatment of the condition, published online in the journal Heart.

Women fared worse than men when it comes to appropriate investigations and treatment, the findings
suggest, although death rates were similar.

In 2006/7, heart failure accounted for more than a quarter of a million hospital deaths and discharges in
England and Wales, equating to around 2.5 million bed days a year and at an annual cost to the NHS of
£563 million.

The authors draw their conclusions from a survey of the first 10 patients admitted each month with a
primary diagnosis of heart failure to 86 hospitals across England and Wales between April 2008 and
March 2009.

During this period, just over 6,000 patients, with an average age of 78, were admitted with the condition.
Almost half of these (43%) were women.

At admission, less than a third (30%) were reported to be breathless at rest and under half (43%) as
having swollen feet/ankles. These are both diagnostic features of heart failure.

Appropriate investigations were not always carried out, the survey shows, with those admitted to general
medical wards less likely to receive these than those admitted to cardiology wards.

Most patients (75%) were given a heart trace monitor test (echocardiogram). But only two thirds of those
(65%) admitted to general medical wards were given this test.

This showed that the left ventricular ejection fraction (LVEF), an indicator of the pump action of one of
the two lower chambers of the heart, was 40% or less in most of those admitted.

But LVEF was not recorded in one in four patients. And those with an LVEF of under 40% or in whom
LVEF was not recorded were more likely to be women, older, and managed on general medical wards.

Levels of natriuretic peptides, which are a much effective test for heart failure, and a much better
barometer of likely outcome than LVEF, say the authors, were only measured in 1% of patients, despite
National Institute of Health and Clinical Excellence recommendations.

Half the patients were admitted to cardiology wards. Compared with those managed on general wards,
they tended to be younger and were more likely to be men. Those admitted to general medical wards
were twice as likely to die as those admitted to cardiology wards, even after taking account of other risk
factors.

While most patients, in whom discharge drug treatment was recorded, were given the appropriate
medicines, only half were prescribed beta blockers. Men and younger patients were more likely to be
given these drugs.

“Currently, hospital provision of care is suboptimal and the outcome of patents poor. The same rules that
apply to suspected cancer should pertain to a disease with such a malign prognosis as heart failure,”
conclude the authors.

This means ready availability of natriuretic peptide testing, prompt referral to a specialist and
appropriately trained staff to manage the condition during and after hospital admission, they say.

[The national heart failure audit for England and Wales 2008-2009 Online First doi:
10.1136/hrt.2010.209171]