Principal results of the Prospective comparison of Angiotensin Receptor neprilysin inhibitor with Angiotensin receptor blocker MEasuring arterial sTiffness in the eldERly - PARAMETER study

Presented at the ESC 2015 by: Bryan WILLIAMS (London, United Kingdom)

Background

Systolic hypertension and increased pulse pressure (PP) are indicative of arterial ageing and large arteries stiffening. Both factors are also predictive of incident cardiovascular disease and heart failure, especially nocturnal hypertension. Large artery stiffness also increases central aortic systolic pressure (CASP) and central aortic pulse pressure (CPP) relative to brachial blood pressure, which increases left ventricular loading conditions and this abnormal ventricular:vascular coupling contributes to the development of heart failure.
LCZ696 is an angiotensin receptor neprilysin-inhibitor (ARNI), developed to combine the protective effect of inhibiting the renin system with potentiating effects of natriuretic peptides. The purpose of the PARAMETER study was to assess both the short and long-term effects (12 and 52 weeks) of LCZ696, compared with olmesartan, an angiotensin receptor blocker, on measures of central aortic hemodynamics and arterial stiffness in older patients with systolic hypertension (>150 mmHg) and an increased PP (>60 mmHg).
454 Patients aged at least 60 years old were, after a wash-out/placebo run-in period (2-4 weeks), randomised to LCZ696 400 mg qd or olmesartan 40 mg qd. After 12 weeks of treatment, additional BP-lowering agents could be added to reach the target of <140/90 mmHg.

Main results

• CASP had lowered from baseline significantly more after 12 weeks of treatment with LCZ696 (-12.6 mmHg) than after olmesartan (-8.9 mmHg, difference: -3.7 mmHg, P=0.01), just like CPP (-6.4 vs. -4.0 mmHg, difference: -2.4 mmHg, P=0.012).
• Brachial systolic blood pressure (SBP) was also significant reduced after 12 weeks, more with LCZ696 than olmesartan (difference: -3,8 mmHg, P=0.016), as was PP (difference: -2.8 mmHg, P=0.013).
• Much of the extra BP-reduction seen with LCZ696 occurred at night, revealed 24-hour ambulatory SBP-monitoring.
• NT-proBNP decreased in 12 weeks, by 34% in the LCZ696 treated group and by 20% in olmesartan-treated patients.
• The difference in reduction of centra land brachial BP in week 52 as compared with baseline was not statistically significantly different between the treatment groups.
• More patients in de olmesartan group received additional BP-lowering agents than in the LCZ696-behandelde groep. Meer mensen in de LCZ696-groep bleven op monotherapie gedurende de studie (68 vs. 53%).
• Safety endpoints occurred at similar rates in both treatment groups.

Conclusie

The PARAMETER study shows for the first time that LCZ696 400 g/dag is more effective than olmesartan 40 mg/dag in lowering both CASP and CPP after 12 weeks of monotherapy in older patients with systolic hypertension and increased pulse pressure. More significant BP-reduction wasa seen in the night-time period.
Since additional BP-lowering agents could be added after week 12, no significant difference was seen in the effect on central and brachial BP. In the olmesartan group, more people had received additional BP-lowering agents.
During the discussion at the press conference Bryan Williams was asked what more he would like to see before this treatment becomes the preferred option for stiffening arteries. He answered that MRI could directly show the distensibility of arteries under influence of these agents. This would be interesting mechanistically, to see whether the observed effect is indeed a consequence of reduced stiffness. The fact that BNP was lower is already direct evidence for this hypothesis, since BNP is released in response to a stiff ventricle.
The observation that BP lowering is most evident at night, indicates that LCZ696 is still effective at that time, even though in this study the agent was given once daily in the morning. This might mean that LCZ696 might also be given once daily for other indications (in many studies it was given twice daily).

- Our reports are based on information made available at the ESC congress -