Lcz696 targets blood pressure and arterial stiffness

The findings, presented today at ESC Congress 2015, show "novel and beneficial effects" of LCZ696 -- an angiotensin receptor/neprilysin inhibitor (ARNI) -- "that may afford greater protection against heart disease, stroke and heart failure than currently available treatment strategies," said Bryan Williams, MD, the study's principal investigator, and Chair of Medicine at University College London, UK.

"An important and unprecedented finding of this trial is that LCZ696 also had an especially powerful effect on reducing night-time blood pressure -- which is a strong predictor of cardiovascular risk," he added.

The PARAMETER study included 454 older patients (mean age 68 years) at high risk of heart failure because of systolic hypertension (HTN) and a wide pulse pressure (PP), which is the difference between the systolic and diastolic pressure readings.

Wide PP is associated with age-related stiffening of the arteries, explained Professor Williams.

"As arteries stiffen, the pressure in the aorta (close to the heart) rises faster than the pressure measured in the arm, and that is the reason we were interested to see if LCZ696 was more effective at reducing this pressure compared to an ARB alone."

Patients were randomised to once daily LCZ696 (200 mg) or olmesartan (20 mg) for 4 weeks, followed by a forced-titration to double the initial doses for the next 8 weeks.

The primary outcome of the study was reduction from baseline to week 12 in central aortic systolic pressure (CASP), with secondary outcomes including reduction from baseline to week 12 in central aortic pulse pressure (CPP) and 24-hour ambulatory brachial and central systolic blood pressure (SBP).

After 12 weeks, patients treated with LCZ696 had a 3.77 mmHg greater reduction in CASP and a 2.4 mmHg greater reduction in CPP from baseline compared to patients treated with olmersartan (P=0.01 and P=0.012 respectively).

The 24-hour ambulatory brachial and central SBPs were significantly reduced from baseline to 12 weeks in both treatment arms, with LCZ696 lowering brachial SBP by an additional 4.1 mmHg and central SBP by an additional 3.3 mmHg compared to olmesartan (P

Add-on hypertension medication was allowed at 12-24 weeks if adequate blood pressure control had not been attained, and a higher percentage of patients treated with olmesartan required add-on medication to improve their blood pressure when compared to patients in the LCZ696 group (47% versus 32%), reported Professor Williams.

Finally, in an exploratory analysis of the carotid-to-femoral pulse wave velocity -- a measure of arterial stiffness -- the researchers noted a trend toward greater improvement in a subgroup of LCZ696-treated patients with the stiffest arteries at baseline.

"This is consistent with our hypothesis that the better reduction in aortic pressure with LCZ696 was related to an improvement in the function of stiffened arteries in older people," he commented.

"PARAMETER is the first randomized study demonstrating the ability of LCZ696 to significantly reduce central blood pressure and pulse pressure, compared to an ARB, in high-risk older patients with systolic HTN and a wide PP," concluded Professor Williams.

Finally, in an exploratory analysis of the carotid-to-femoral pulse wave velocity -- a measure of arterial stiffness -- the researchers noted a trend toward greater improvement in a subgroup of LCZ696-treated patients with the stiffest arteries at baseline.

"This is consistent with our hypothesis that the better reduction in aortic pressure with LCZ696 was related to an improvement in the function of stiffened arteries in older people," he commented.

"PARAMETER is the first randomized study demonstrating the ability of LCZ696 to significantly reduce central blood pressure and pulse pressure, compared to an ARB, in high-risk older patients with systolic HTN and a wide PP," concluded Professor Williams.

"These data are important because lowering systolic and pulse pressure in older people with stiffened arteries is an unmet need in our endeavour to reduce the risk of cardiovascular disease and heart failure in older people. Our results suggest that LCZ696 has been able to achieve more in this regard than existing treatments, it is an exciting advance."