The path to a drug that can reverse heart failure is littered with disappointment. As it stands, a physician can choose to give diuretics, blood pressure drugs or diabetes medication to people who suffer from chronic heart failure but these agents treat only the symptoms, not heart failure itself. Hopes soared in the 1980s when inotropic drugs, which help the heart muscles contract, improved patients’ ability to exercise but were later linked to increased risk of cardiac arrest. Large trials testing two blood pressure medications, candesartan and irbesartan, had less-than-encouraging outcomes. So researchers are interested in seemingly positive results announced yesterday at the European Society of Cardiology Congress meeting and concurrently published in The Lancet.
The study, funded Swiss drugmaker Novartis, found that taking a drug called LCZ696 for three months reduced levels of an established biomarker for heart failure, an inert molecule called N-terminal proBNP peptide (NT-proBNP), by an average of 23% among individuals with diastolic heart failure—a condition in which the heart muscle relaxes too much between beats. In contrast, the comparison group, which received valsartan, a blood pressure medication Novartis makes under the trade name Diovan, saw only a 3% average reduction. The 300-person, phase 2 trial also revealed that the group receiving LCZ696 experienced a decrease in size of the heart’s left atrium—a good thing as it indicates the organ has become more efficient at pumping out blood to the body.
“Our data make a strong argument for testing this hypothesis in a large outcomes trial to determine if it is indeed effective at reducing morbidity and mortality in this disorder with a large unmet need,” says cardiologist Scott Solomon at Brigham and Women’s Hospital in Boston, who led the Novartis-funded trial.
In heart failure, which affects an estimated 2% of the US population, heart muscle cells release a hormone called brain natriuretic peptide (BNP), a natural defense against tissue scarring and that also helps the body get rid of excess sodium, thereby preventing high blood pressure. Unfortunately, an enzyme called neprilysin degrades BNP, thus preventing it from doing its beneficial work.
LCZ696 has two molecular components, one of which that inhibits neprilysin, allowing BNP to provide a boost to the heart. The other element of the drug blocks receptors for the hormone angiotensin II, preventing it from restricting blood vessels and causing high blood pressure.
Although this study produced positive results, it is still only at the very beginning of showing any promise. “This is a good start,” says John Cleland, a cardiologist at the Castle Hill Hospital in nearby Hull, UK, who wrote the accompanying editorial in the journal. The trouble, he explains, is that to date, no large-scale trial has established the efficacy of LCZ696 in diastolic heart failure. Novartis is already plowing ahead with an 8,000-person phase 3 trial testing LCZ696 against enalapril manufactured by Merck under the trade name Vasotec, an angiotensin-converting enzyme (ACE) inhibitor, but, importantly, that trial will focus on patients with systolic heart failure, where the heart has trouble contracting.
A future trial on LCZ696 for diastolic heart failure would also do well to focus on quality of life indicators in its primary study goals, explains Dalane Kitzman, cardiologist at Wake Forest Baptist Medical Center in Winston-Salem, North Carolina. He adds that while the reduction in biomarker protein levels is very encouraging, quality of life measures did not improve in the LCZ696 trial. “One of the main things patients want to know is—will this drug make me feel better?” Kitzman says, referring to quality of life.
Both cardiologists also point to the somewhat worrying trend that valsartan performed almost as well as LCZ696 at the end of the nine-month trial. This could mean that valsartan works just as well as the new drug, but more slowly. Kitzman says LCZ696 should still be tested in a large trial, and adds that researchers should bear in mind the stories of previous heart failure agents when considering study results of new potential ones. “The history of heart failure treatment is checkered with many surprising reversals and unexpected outcomes.”
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