初めてのアンジオテンシン受容体ネプリライシン阻害薬は有望であることが示された

PARAMOUNT：新しいクラスの初めての薬剤であるアンジオテンシン受容体ネプリライシン阻害薬の、心駆出能の保たれた心不全患者に対する有効性が示された
PARAMOUNT: Efficacy found for a first-in-class angiotensin receptor neprilysin inhibitor in patients with heart failure and preserved ejection fraction
新たなアンジオテンシン受容体ネプリライシン阻害薬LCZ696は心駆出能の保たれた心不全（HfpEF）患者に有益であることが示されたとの PARAMOUNT（Prospective compArison of ARNI with ARB on Management Of heart failUre with preserved ejectioN fracTion）トライアルの結果が2012年European Society of Cardiology学会で発表され、同時にLancetオンライン版に掲載された。トライアルの結果とともに発表された背景情報によると、駆出率の低下した心不全に対する薬物療法の有益性は多くのスタディで示されているが、最新のESCガイドラインでは HfpEFの死亡率および罹患率を低下させる治療は未だ示されていないとされる。13か国308人の患者を対象として施行された第II相試験である PARAMOUNTスタディは、新たなアンジオテンシン受容体ネプリライシン阻害薬LCZ696とARBバルサルタンのナトリウム利尿ペプチド濃度に対す る効果を比較した。このスタディで調査したナトリウム利尿ペプチドNT-proBNPは、心臓の壁ストレスのマーカーであり心不全患者においてその値が上 昇している。スタディの結果、LCZ696はバルサルタンよりもNT-proBNPレベルを23%低下させたことが示された。LCZ696はまた、左房の 拡大を軽減させ心不全症状を改善した。
Full Text

The novel angiotensin receptor neprilysin inhibitor, LCZ696, demonstrated beneficial effects in heart failure patients with preserved ejection fraction (HFpEF), according to results of the PARAMOUNT (Prospective compArison of ARNI with ARB on Management Of heart failUre with preserved ejectioN fracTion) trial.  The study results were presented in a Hotline session at ESC Congress 2012 and published simultaneously online in the Lancet. 

Approximately half of all heart failure patients have normal or nearly normal ejection fraction. However, while many studies have shown a benefit of pharmacological therapies in heart failure with reduced ejection fraction, so far, according to the latest ESC heart failure guidelines, no treatment has been shown to reduce mortality or morbidity in HFpEF.

The PARAMOUNT study, a phase II trial conducted in 308 patients in 13 countries, compared the effects of LCZ696, a new angiotensin receptor neprilysin inhibitor, and the ARB valsartan on the concentrations of natriuretic peptides. The natriuretic peptide investigated in this study, NT-proBNP, is a marker of cardiac wall stress, and levels are increased in patients with heart failure.

Study results presented at ESC Congress 2012 showed that LCZ696 reduced levels of NT-proBNP by 23% when compared with valsartan. LCZ696 also reduced enlargement of the left atrium, another marker of adverse outcomes in heart failure, and improved the symptoms of heart failure.

According to the study's lead author Professor Scott Solomon, Professor of Medicine at Harvard Medical School and Director of Noninvasive Cardiology at Brigham and Women's Hospital, Boston, LCZ696 acts by inhibiting both the angiotensin receptor and the enzyme responsible for the breakdown of the natriuretic peptides (neprilysin). LCZ696's dual mechanism of action thus acts to restore the altered neurohormonal balance in HFpEF. Earlier research has suggested that the clinical benefits derived from neprilysin inhibition may be best achieved if the renin-angiotensin system is simultaneously inhibited.

"LCZ696 is unique in simultaneously blocking the renin angiotensin system while augmenting the body's intrinsic natriuretic peptide system through neprilysin inhibition," said Professor Solomon. "These dual effects may be important in the treatment of HFpEF. 

"LCZ696 in the PARAMOUNT study is the first compound to show both reductions in NT-proBNP and left atrial size in HFpEF patients, each powerful predictors of outcome in heart failure. The favorable effects of LCZ696 seen in patients with HFpEF in PARAMOUNT are encouraging, and further testing of this agent in this patient population is warranted." 

The PARAMOUNT study was sponsored by Novartis.