PARAMETER: LCZ696 Bests Olmesartan in Decreasing Arterial Stiffness in Elderly

LONDON, UK — Although the drug widely known as LCZ696 (valsartan/sacubitril [Entresto, Novartis]) was approved recently in the US to treat patients with heart failure, it may also be beneficial in lowering arterial stiffness in older patients, suggests new research^[1].

The multicountry study, called the Prospective Comparison of an Angiotensin-Receptor Neprilysin Inhibitor With an Angiotensin-Receptor Blocker Measuring Arterial Stiffness in the Elderly (PARAMETER), included 454 patients with both systolic hypertension and increased pulse pressure, a marker for arterial aging and stiffening. Those taking the ARNI LCZ696 had significantly greater changes in central aortic systolic pressure (CASP), central aortic pulse pressure (CPP), and brachial systolic blood pressure at 12 weeks compared with those taking the ARB olmesartan.

"The PARAMETER study met its primary and key secondary objectives by demonstrating superior efficacy of LCZ696," said lead author Dr Bryan Williams (University College London, UK) during a prepresentation press conference here at the European Society of Cardiology (ESC) 2015 Congress.

He noted that "at least from a mechanistic point of view," future research using MRI "will enable us to confirm or refute whether or not these impressive changes in . . . these patients are associated with a direct effect on the thickness and functionality of the aorta."

Measuring Hemodynamics, Arterial Stiffness

"Large-artery stiffness . . . increases CASP and CPP relative to brachial blood pressure, which increases left ventricular loading conditions," explained Williams. "And this abnormal vascular/vascular coupling contributes to the development of heart failure."

He noted that the purpose of PARAMETER was to compare the ARNI with the ARB both short and long term on "measures of central aortic hemodynamics" and arterial stiffness.

The patients, who were enrolled at 48 sites in 12 countries, had systolic blood pressure >150 mm Hg and wide pulse pressure >60 mm Hg. They were randomly assigned to receive once-daily LCZ696 200 mg (n=229) or olmesartan 20 mg (n=225) for the first 4 weeks, followed by a forced titration of a doubling of the initial dose for 8 more weeks. During the next 40 weeks, additional drugs could be added if BP weren't at goal.

The ARNI group had significantly reduced CASP after 12 weeks of treatment vs the olmesartan group, meeting the primary end point (-12.6 vs -8.9 mm Hg, respectively, P=0.01).

Those receiving LCZ696 also had greater reductions at 12 weeks in CPP (-6.4 vs -4 mm Hg, respectively, P=0.01), brachial systolic BP (-13.7 vs -9.9, P=0.02), and pulse pressure (-7.7 vs -4.9, P=0.01).

Williams noted that the greater changes in 24-hour brachial and central aortic systolic BP for the LCZ696 group (both P<0.001), especially at night, were a pleasant surprise. "Nighttime is a period that is known to be associated with increased cardiovascular risk when blood pressure is elevated," he said.

"Real Potential"

The 52-week follow-up showed that the ARNI group again had greater changes than the ARB group in CASP, CPP, and brachial BP, as well as 12-week and 52-week pulse-wave velocity, but the differences were not significant.

When researchers examined use or no use of add-on antihypertensive medications, 68% of the LCZ696 group were able to stay on monotherapy vs 53% of the olmesartan group. In addition, significantly more of the olmesartan group added on amlodipine and or hydrochlorothiazide (P=0.002).

Finally, there were no significant between-group differences in key safety parameters, including deaths, any adverse events, serious adverse events, or discontinuations due to any adverse event.

"PARAMETER is the first randomized study to demonstrate the ability of LCZ696 to reduce central BP and pulse pressure more effectively than an ARB in high-risk older patients," said Williams. "These results suggest that it could provide a therapeutic advantage beyond those observed with renin-angiotensin-aldosterone system blockade alone."

Session comoderator Dr Steen Dalby Kristensen (Aarhus University, Skejby, Denmark) told heartwire from Medscape that the findings show that the new ARNI "really has potential in hypertension in elderly patients."

He added that with some promising new research on old HF drugs, including spironolactone, and on new drugs such as LCZ696, it's a good time for the field. "I think all of this is really very interesting. And it will be interesting to see how this is implemented in future guidelines."

Williams reported receiving honoraria from Novartis for lectures. Kristensen reported no relevant financial relationships.

Heartwire from Medscape © 2015  Medscape, LLC

Cite this: PARAMETER: LCZ696 Bests Olmesartan in Decreasing Arterial Stiffness in Elderly - Medscape - Sep 01, 2015.