Chronic heart failure and the Paradigm-HF Trial

Chronic heart failure is a progressive, debilitating disease where the heart is unable to pump enough blood throughout the body. Symptoms such as breathlessness, fatigue and fluid retention can appear slowly and worsen over time, significantly impacting quality of life.

More 20 million people in the United States and European Union live with heart failure, facing a high risk of death and poor quality of life, despite currently available medicines.

Pardigm-HF is the largest-ever trial of a heart failure treatment, specifically designed to assess Novartis' LCZ696 in patients with chronic systolic heart failure. The five-year, phase III study involved 8,442 patients at 1,043 study sites in 47 countries.

The trial's data monitoring committee unanimously recommends early closure after confirming that LCZ696 delayed cardiovascular death and reduced heart failure hospitalizations when compared to vs. Enalapril, an angiotensin converting enzyme inhibitor or ACE-I drugs.

Because of the positive results in the Paradigm trial for systolic heart failure, Novartis already has commenced a "sister" study, titled "Paragon," for chronic diastolic heart failure patients. Paragon is expected to take five years to conduct.

Sources: Centers for Disease Control and Prevention; American College of Cardiology; Clincaltrials.gov.

Today a Medical University of South Carolina researcher will be among an executive team announcing the development of what is being hailed as the first breakthrough drug for chronic heart failure in nearly a decade.

The drug, called LCZ696, is expected to "fundamentally change the current treatment of chronic heart failure patients," according to MUSC's Dr. Michael Zile, an international investigator for a study titled, "Paradigm-HF."

The drug has not been approved by the Food and Drug Administration, but Zile expects it will be and likely be on the market by the end of 2015. The drug is made by Novartis, which is headquartered in Basel, Switzerland,

The five-year, phase III study involved 8,442 patients at 1,043 study sites in 47 countries. It found that the new drug dramatically prolonged survival, improved exercise tolerance and prevented repetitive hospitalizations. The trial found the new drug to be so successful, it was ended early.

"For the first time in more than a decade, the development of LCZ696 will give physicians the opportunity to improve current standards of care and help chronic heart failure patients live longer, better, and more productive lives," said Zile, who is in Barcelona, Spain, for the European Society of Cardiology Congress for the announcement.

The unveiling will coincide with the publication of the study results in the New England Journal of Medicine, likely making headlines nationally and internationally.

According to the Centers for Disease Control and Prevention, chronic heart failure is a progressive, debilitating disease where the heart is unable to pump enough blood throughout the body. Symptoms such as breathlessness, fatigue and fluid retention can appear slowly and worsen over time, significantly impacting quality of life.

Heart failure is a significant and growing public health concern with more 20 million people living with the disease across United States and Europe. It continues to be associated with high morbidity and mortality, frequent hospitalization and poor quality of life, despite currently available medicines. The disease's economic burden worldwide is estimated to exceed $45 billion annually.

Dr. Adrian Van Bakel, a MUSC cardiologist specializing in heart failure but with no ties to the study, describes heart failure as "epidemic" and that millions of Americans have it.

"It is probably one of the most prevalent chronic diseases that we have," said Van Bakel, adding that it is often the end result of other diseases. "For instance, having high blood pressure over a long period of time can cause heart failure. Coronary artery disease and subsequent heart attacks can cause heart failure."

Van Bakel said the global cardiology community is keenly aware of LCZ696 and its promise for a better future for those suffering from heart failure, but stressed it is not a cure.

"We're still not curing heart failure. It's not a cure, but we hope to continue to delay progression and have people live longer with this chronic disease," he said.

In fact, the drug for now is for one type of heart failure patient, those with basically weakened hearts that don't pump blood well, those with systolic heart failure or reduced ejection fraction. The other group is people with weakened hearts that don't fill up with blood adequately, those with diastolic heart failure or preserved ejection fraction.

Because of the positive results in the Paradigm trial for systolic heart failure, Novartis already has commenced a "sister" study, titled "Paragon," for diastolic heart failure patients. Paragon is expected to take five years to conduct and MUSC is an enrollment site. Zile is a member of the study's steering committee.

As for those with systolic heart failure, the current evidence-based guidelines for treatment called for blocking hormones that cause a constriction of blood vessels.

"When the heart doesn't pump well," said Van Bakel, "that particularly affects a lot of things in the kidney. So what happens is that the body starts what we call neural hormonal feedback loops.

"One is called the renin-angiotensin-aldosterone system. That gets activated in heart failure. It causes constriction of all the peripheral blood vessels. You have a weak heart trying to pump against higher resistance."

Blocking that process involved using angiotensin converting enzyme inhibitors, or ACE-I drugs, or angiotensin receptor blockers, or ARB drugs.

Zile said the Paradigm study directly compared the use of LCZ696 to ACE-I in patients with (systolic heart failure) and proved that LCZ696 improved survival and decreased disability compared to ACE-I drug, Enalapril (marketed as Vasotec in the U.S.)

"Based on this, there will be a 'paradigm' shift in treatment of chronic heart patients in which LCZ696 will replace ACE-I and ARBs as the cornerstone of treatment for (systolic heart failure)," said Zile, adding that LCZ696 has "a very low side effect profile."

"There are fewer episodes of kidney dysfunction, abnormal electrolytes and cough (when LCZ696 is compared to Enalapril," said Zile.

Van Bakel agreed, adding that ACE-I drugs didn't work as well in African-Americans as compared to Caucasians. He also said the combination of using ACE-I drugs in combination with beta blockers, designed to block the sympathetic nervous systems, often resulted in low blood pressure.

"As a clinician, putting people on all those drugs is often limited by low blood pressure. Not everyone can tolerate it. All of these medicines dilate the blood vessels and the blood pressure drops, he said.

Van Bakel said LCZ696 is a combination of the ARB drug, the generic Valsartan, and a new compound that targets a whole different hormonal feedback loop, called the natriuretic peptide system.

The system causes the blood vessels to dilate and improves urine output, which is a good function for heart failure patients, said Van Bakel.

Reach David Quick at 937-5516.