NEW HORIZON IN HEART FAILURE INVESTIGATIONAL DRUG POISED TO CHANGE CARDIOLOGY

An investigational new heart failure drug could be poised to change the face of cardiology based on Hot Line results presented today at ESC Congress 2014

Findings from the PARADIGM-HF trial, published simultaneously in the New England Journal of Medicine, "are extraordinarily powerful and compelling; they are destined to change the management of patients with chronic heart failure for years to come," said Milton Packer, MD, co-primary author of the study from University of Texas Southwestern Medical Center, in Dallas, Texas USA.

"This really is an astonishing result and a real breakthrough for patients with heart failure," added John McMurray, MD, the other co-primary author, from the University of Glasgow, UK.

The new agent, an angiotensin receptor-neprilysin inhibitor (ARNI) known as LCZ696, has already been granted Fast Track status by the United States Food and Drug Administration (FDA) -- a designation which can expedite the review of new medicines intended to treat serious or life-threatening conditions. Fast Track designation also allows for rolling submission in the US, which Novartis said it expects to complete by the end of 2014. The company said it aims to file in Europe in early 2015.

"To say that we are excited is an understatement. We are absolutely thrilled," said Dr. Packer.

"Given the survival advantage of LCZ696 over currently available drugs, once this drug becomes available, it would be difficult to understand why physicians would continue to use traditional angiotensin converting-enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) for the treatment of heart failure."

PARADIGM-HF (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure) first made headlines this spring when the trial was stopped early by an independent data monitoring committee based on evidence of the "overwhelming benefit" of LCZ696 compared to enalapril, an ACE inhibitor.

"We were surprised and delighted that the magnitude of the superiority was so great that the trial was stopped early by the ethical committee. That was an amazing event," said Dr. Packer.

Today, full details of the findings are being released for the first time.

"The magnitude of the advantage of LCZ696 over enalapril on cardiovascular mortality was at least as large as that of enalapril over placebo during long-term treatment," Dr. Packer reported. "This robust finding provides strong support for using this new approach instead of ACE inhibitors or ARBs in the treatment of chronic heart failure."

PARADIGM-HF randomized 8,399 patients with class II to IV heart failure and an ejection fraction if 40% or less to either LCZ696 200 mg twice daily (n=4,187), or enalapril 10 mg twice daily (n=4,212), in addition to recommended therapy.

When the trial was stopped early, after a median follow-up of 27 months, death from cardiovascular causes or hospitalisation for heart failure (the primary composite outcome) had occurred in 21.8% of the LCZ696 group and 26.5% of the enalapril group (hazard ratio [HR] 0.80; p=0.0000002).

Compared to enalapril, LCZ696 reduced the risk of death from cardiovascular causes by 20% (13.3% vs 16.5%; HR 0.80; p<0.0001), and the risk of hospitalisation for heart failure by 21% (12.8% vs 15.6%; HR 0.79; p<0.0001), noted Dr. Packer. This effect was consistent across all prespecified subgroups.

Secondary outcomes were also significantly improved by LCZ696, including all-cause mortality (17.0% vs 19.8%; HR 0.84; p<0.001) and symptoms and physical limitations of heart failure measured on the Kansas City Cardiomyopathy Questionnaire (p=0.001).

"The superiority of LCZ696 over enalapril was not accompanied by important safety concerns," added Dr. Packer. The LCZ696 group had more symptomatic hypotension compared to the enalapril group (14% vs 9.2%, p< 0.001) however this rarely required the discontinuation of treatment. In fact, fewer patients in the LCZ696 group stopped their study medication for any adverse event (10.7% vs 12.3%, P=0.03).

Importantly, LCZ696 was not associated with an increased risk of serious angioedema, which was the main safety concern observed with a related medication -- omapatrilat -- in the OVERTURE trial.

Omapatrilat's association with life-threatening angioedema is related to its inhibition of ACE, neprilysin and aminopeptidase P, whereas LCZ696 avoids inhibition of ACE and aminopeptidase P. "LCZ696 was specifically designed to minimise the risk of serious angioedema by combining the neprilysin inhibitor sacubitril (AHU377) and the ARB valsartan," explained Dr. Packer.

Findings of the PARADIGM-HF trial are particularly striking when considered in the context of the current standard of care in heart failure, concluded Professor McMurray.

"The superiority of LCZ696 wasn't over placebo -- it was over the gold-standard dose of the gold-standard ACE inhibitor, the absolute corner-stone of guideline-recommended, conventional therapy," he said. "On top of that, these incremental benefits were obtained in patients fully treated with the other key pharmacological therapies for this condition such as beta-blockers and mineralocorticoid receptor antagonists. All that you can ask of any new therapy in heart failure (or other chronic diseases) is to make patients live longer, stay out of hospital and feel better -- and those are exactly the benefits we demonstrated with LCZ696."

Bleeding Heart

Bleeding Heart. Truly one of the most moving and vulnerable looking flowers in the whole plant Queendom.

PNEUMONIA BACTERIUM LEAVES TINY LESIONS IN THE HEART

The long-observed association between pneumonia and heart failure now has more physical evidence, thanks to research in the School of Medicine at The University of Texas Health Science Center at San Antonio.

The researchers found proof that Streptococcus pneumoniae, the leading cause of community-acquired pneumonia, actually physically damages the heart. The bacterium leaves tiny lesions that researchers detected in mouse, rhesus macaque and human autopsy tissue samples.

"If you have had severe pneumonia, this finding suggests your heart might be permanently scarred," said study senior author Carlos Orihuela, Ph.D., associate professor of microbiology and immunology at the UT Health Science Center San Antonio.

It's not yet known whether the small lesions contribute to increased risk of death in humans or if the scarring that occurs afterward is permanent, ultimately diminishing cardiac function in individuals who have recovered from a severe infectious disease episode. The team will study the long-term ramifications in non-human primates at the Texas Biomedical Research Institute's Southwest National Primate Research Center.

Streptococcus pneumoniae in the blood invaded the heart and formed lesions in the myocardium, the muscular middle layer of the heart wall, the researchers showed. The team identified mechanisms by which the bacterium is able to spread across endothelial cells in cardiac blood vessels to travel to and infect the heart.

"Fortunately, we have a candidate vaccine that can protect against this," Dr. Orihuela said. The Health Science Center, St. Jude's Children's Research Hospital in Memphis, Tenn., and the University of Oklahoma have claimed intellectual property protection on the vaccine project. The candidate vaccine acts to stop both the movement of the infection into the heart and the toxin that kills heart muscle cells called cardiomyocytes. The vaccine protected immunized animals against cardiac lesion formation, the study showed.

Study limitations included the small sample size of human tissues analyzed, the researchers noted. The American Heart Association and the National Institutes of Health funded the project. The journal PLoS Pathogen published the study online Sept. 18.

ANTIBIOTIC MIGHT RAISE HEART RISKS

Taking the widely used antibiotic clarithromycin may boost some patients’ odds of dying from heart-related causes, a new study suggests.

Because millions of people receive this antibiotic each year, the findings require urgent confirmation, said the Danish researchers behind the study. However, they emphasized that the actual risk is small and that guidelines for the use of the drug should not be changed until more information is available.

One heart expert wasn’t surprised by the finding, however.

“Some commonly used antibiotics should be taken with caution, especially for those people who are at risk for heart disease,” said Dr. Suzanne Steinbaum, a preventive cardiologist at Lenox Hill Hospital in New York City.

“As it has been shown before, not all antibiotics are created equal when it comes to increasing the risk of cardiovascular death,” she said. “If you have an underlying heart condition, be certain to discuss it with your doctor before taking an antibiotic prescription. There are definitely safer alternatives.”

Clarithromycin and another antibiotic called roxithromycin belong to a group of antibiotics called macrolides. It’s believed that macrolides increase the risk of potentially deadly heart rhythm problems, the Danish researchers explained.

In the study, they analyzed more than 5 million courses of antibiotic treatment with clarithromycin, roxithromycin, or penicillin V given to Danish adults, aged 40 to 74, between 1997 and 2011.

During this period, 285 cardiac deaths occurred — 18 during the use of clarithromycin and 32 during the use of roxithromycin. After adjusting for other factors, the researchers concluded that ongoing use of clarithromycin was associated with a 76 percent higher risk of cardiac death, compared with the use of penicillin V.

The absolute risk difference was 37 cardiac deaths per 1 million courses with clarithromycin. The authors noted that there was no heightened risk of cardiac death after treatment with clarithromycin stopped.

Ongoing or past use of roxithromycin was not associated with increased risk of cardiac death, according to the study published online Aug. 19 in BMJ.

The study is “the first large-scale population-based observational study to show significantly increased cardiac risk with clarithromycin and the relative cardiac safety of roxithromycin,” wrote a team led by Henrik Svanstrom of the Statens Serum Institut in Copenhagen.

Because the study was observational in nature (looking over past data), it could not prove a cause-and-effect relationship. However, an expert familiar with antibiotics said the findings are worthy of concern.

Although the risk to any one patient remains very small, “it should still be considered by physicians before prescribing this antibiotic,” said Dr. Ambreen Khalil, an infectious disease specialist at Staten Island University Hospital in New York City. “Patients with underlying heart conditions who are taking medications that affect the heart rhythm may be particularly vulnerable,” she said.