BARCELONA – The novel investigational agent LCZ696 – now grabbing attention for its dramatic mortality benefit in patients with heart failure with reduced ejection fraction – also appears to have a bright future as an antihypertensive medication.
LCZ696, a first-in-class ARNI, or angiotensin receptor neprilysin inhibitor, showed impressive blood pressure–lowering efficacy in obese and overweight hypertensive patients in a pair of 8-week, randomized, double-blind, controlled clinical trials presented at the annual congress of the European Society of Cardiology.
Bruce Jancin/Frontline Medical News
LCZ696 appears to have a bright future as an antihypertensive medication, researchers at the European Society of Cardiology said.
In another hypertension study presented at the meeting, LCZ696 added to amlodipine resulted in blood pressure control as defined by values below 140/90 mm Hg in 68.5% of Asian patients with uncontrolled hypertension on amlodipine monotherapy.
LCZ696 comprises sacubitril, which boosts levels of endogenous vasoactive peptides by inhibition of neprilysin, in combination with the angiotensin receptor blocker valsartan.
Dr. Luis M. Ruilope presented the pooled results of two multicenter, randomized, 8-week, double-blind trials in a total of 848 patients with mild to moderate hypertension, of whom 347 were obese, 368 were overweight, and 133 were normal weight. Participants were randomized to once-daily oral LCZ696 at 400 mg or valsartan at 320 mg.
LCZ696 proved more effective than valsartan in lowering 24-hour ambulatory blood pressure, as well as office blood pressure and pulse pressure, in all three patient groups. In obese patients, for example, LCZ696 reduced mean office systolic blood pressure by 7.5 mm Hg more than did valsartan, mean office diastolic blood pressure by 2.9 mm Hg more, and mean office pulse pressure by 4.6 mm Hg more. Both drugs were generally well tolerated and were free of serious side effects.
It was important to demonstrate LCZ696’s efficacy in these studies of overweight and obese patients because heavy patients comprise a key segment of the hypertensive population. Indeed, hypertension is roughly twice as prevalent in obese as in nonobese individuals, noted Dr. Ruilope, who os the head of the hypertension unit at the Hospital 12 de Octubre, Madrid.
Separately, Dr. Jiguang Wang of the Shanghai (China) Institute of Hypertension presented an 8-week, double-blind, multicenter clinical trial in which 266 Asian patients with systolic hypertension not controlled with amlodipine monotherapy were randomized to LCZ696 at 200 mg/day plus amlodipine at 5 mg/day, or to amlodipine alone at 5 mg/day.
Importantly, all subjects had hypertension previously uncontrolled with amlodipine. This is a common situation in Asian populations, in whom calcium channel blockers such as amlodipine often activate both the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system, thereby limiting treatment efficacy. The hypothesis underlying this study was that the neprilysin inhibition achieved by adding the ARNI to amlodipine would counteract the sympathetic and RAAS activation, with resultant greater blood pressure–lowering efficacy, Dr. Wang explained.
Over the course of 8 weeks, mean 24-hour ambulatory systolic blood pressure dropped significantly, by 13.9 mm Hg from a baseline of 139 mm Hg in patients treated with LCZ696 added on to amlodipine, compared with a 0.8–mm Hg decrease in patients on amlodipine only. Control of sitting systolic blood pressure was achieved in 72% of the combination therapy group compared to 35% on amlodipine monotherapy.
LCZ696 was the talk of ESC 2014 as a consequence of its impressive performance in the landmark PARADIGM-HF trial, in which it reduced the relative risks of cardiovascular death and hospitalization for heart failure by 20% and 21%, respectively, in patients with heart failure with reduced ejection fraction on optimal background therapy.
Dr. Ruilope and Dr. Wang reported receiving consulting fees from Novartis, which funded the studies and is developing LCZ696 for the marketplace.