Table 2.

Exemplar pharmaco-therapeutic randomized controlled trials beyond low-density lipoprotein cholesterol lowering to delay calcific aortic valve disease progression

Trial name, year registered	Key inclusion criteria	Primary outcome measure	Secondary outcome measures	Agent/pathways targeted	Status/major findings
ALFA,39 2012	Normotensives aged 20–75 years Peak aortic jet velocity of 3.0–4.5 m/s, mean pressure gradient of 25–49 mmHg or AVA 0.76–1.5 cm2 NYHA functional class <III	Change of VO2max in cardiopulmonary exercise test	Change of peak aortic jet velocity in echocardiography Change of mean pressure gradient across AV Diastolic function—LV area (cm2), E/E' value LV mass index Development of AS symptoms or LVEF <50% AVR 6-min walk distance Adverse events Safety endpoint	Fimasartan vs. placebo AT-II antagonism	Unknown
AVADEC,40 2017	Participants in the Danish Cardiovascular Screening Trial AV calcification score >300 AU, but without AS	Change in AV calcification	Change in compiled arterial calcification (CT) Change in aortic diameter Change in plaque burden in coronary and carotid arteries (CT) Change in AVA (echocardiography) Change in bone mineral density (CT) Change in MGPs and osteocalcin Change in quality of life	Menaquinone-7 plus vitamin D vs. placebo MGP activation	Ongoing
BASIK-2,41 2016	BAV Calcified mild to moderate AS on prior echocardiography	Change in AV calcium metabolism (18F-NaF PET/CT)	Change in AV calcium score (CT) Progression of AS (echocardiography)	Vitamin K2 vs. placebo MGP activation	Ongoing
CAVS,42 2015	Age >50 years AVA >1.0 cm2 but <2.0 cm2 AV calcium >300 AU (CT) EF >50%	Changes in aortic valve calcium levels (CT)	Change in levels of plasma interleukin-6 Change in AV function: AVA/mean transvalvular pressure gradient Change in LV function Change in plasma tumour necrosis factor alpha	Ataciguat (HMR-1766) vs. placebo Nitric oxide-independent soluble guanylate cyclase activator	Completed
CaLIPSO,43 2016	Aged 18–80 years CAC volume score 100–3500 AU (Agatston score) Either ≥55years or history of diabetes mellitus On haemodialysis for ≥6 months	Change in log CAC volume score from baseline to Week 52 for the combined dose groups vs. placebo	Change in log CAC volume score Change in log CAC Agatston score Number of subjects with <15% progression in CAC Agatston score Number of subjects with ≥15% progression in CAC Agatston score Change in log thoracic aorta calcification volume score Change in log thoracic aorta calcification Agatston score Change in log AV calcification volume score Change in log AV calcification Agatston Number of participants with the composite safety endpoint Mortality rate (all-cause)	SNF472 (myo-inositol hexaphosphate) vs. placebo Selective inhibition of hydroxyapatite crystal formation	Published44 SNF472 attenuated the progression of AV calcification in patients with end-stage kidney disease receiving haemodialysis (14% vs. 98%; P < 0.001)
DECAV-K2,45 2017	AV calcium score >300 Absence of AS requiring operation	Hemodynamic disease progression on echocardiography (change in pressure gradients, AVA, peak aortic jet velocity)	Activation of the MGP Change in AV calcification (CT) Improvement of dyspnoea Improvement of the quality of life	Menaquinone-7 plus vitamin D3 vs. vitamin D3 MGP activation	Recruiting
DIP-CAVD,46 2019	Patients aged >19 years 2.0 m/s ≤ peak aortic jet velocity <4.0 m/s OR AV calcium score ≥300 AU on echocardiography/CT	Change in AV calcium volume (96 weeks)	Change in aortic valve calcium volume change (48 weeks) Change in aortic valve calcium score (48 weeks, 96 weeks) Relative change in aortic valve calcium volume (48 weeks, 96 weeks)	DA-1229 at two different dosages vs. placebo Attenuated DPP-4-dependent insulin-like growth factor-1 inhibition	Recruiting
EAVaLL,47 2014	Age >50 and <85 years Aortic sclerosis (thickening or calcification of aortic leaflets with normal leaflet excursion and peak aortic jet velocity <2 m/s) OR mild AS (peak aortic jet velocity 2–3 cm/s, AVA >1.5 cm2, mean gradient <25 m) Lp(a) >50 mg/dL	Calcium score progression by cardiac CT	Mean change in Lp(a) levels Rates of valve disease progression (echocardiography) Drug compliance Side effects and adverse event	Niacin vs. placebo Downregulation of the transcriptional activity of the LPA promoter; Attenuated apoB100 synthesis	Unknown
PCSK9 Inhibitors in the Progression of Aortic Stenosis,48 2017	Mild-to-moderate AS	Progression of calcium score (CT and NaF-PET)	Efficacy of inhibition in calcium score progression (Agatston score) by the presence of Lp(a) SNPs Mean change in Lp(a) levels between treatment arms Mean change in lipid panel Change in AVA (echocardiography) Change in aortic valve peak velocity (echocardiography) Adverse events	PCSK9 inhibitor vs. placebo PCSK-9 inhibition/LDL-C and Lp(a) lowering	Unknown
SALTIRE-II,49 2014	Age >50 years Peak aortic jet velocity >2.5 m/s on echocardiography Grade 2–4 calcification of the AV on echocardiography	Change in AV calcium score	Change in AV 18F-NaF uptake Change in aortic jet velocity Change in thoracic aortic and CAC score Change in thoracic spine bone mineral density Change in quality of life determined by Short Form Questionnaire	Alendronic acid vs. placebo; Denosumab vs. placebo Inhibition of osteoclast-mediated bone-resorption; RANKL inhibition	Published38 Neither denosumab nor alendronic acid affected AV calcification, peak aortic jet velocity or 18F-NaF aortic valve uptake at 24 months
SLOW,50 2020	Asymptomatic AS AVA >1 cm2 Peak aortic jet velocity <4 m/s	Change in AV calcification (MSCT) Correlation with mitral annulus and ascending aorta calcification	N/A	Menaquinone vs. placebo MGP activation	Recruiting
Vitamin K Supplement for Inhibition of the Progress in Aortic Valve Calcification,51 2008	Peak aortic jet velocity >2 m/s on echocardiography eGFR ≥60 mL/min/1.73 m2 Not on VKA	Change in AV calcium score	Changes of dp-ucMGP plasma levels	Phytomenadione vs. placebo MGP activation	Published52 Vitamin K attenuated AV calcium volume score progression in patients with AS (10.0% vs. 22.0%; P < 0.001)

AS, denotes aortic stenosis; AU, arbitrary units; AV, aortic valve; AVA, aortic valve area; AVR, aortic valve replacement; BAV, bicuspid aortic valve; CAC, coronary artery calcium; CT, computed tomography; EF, ejection fraction; eGFR, estimated glomerular filtration rate; NYHA, New York Heart Association; Lp(a), lipoprotein (a); LDL-C, low-density lipoprotein cholesterol; LV, left ventricular; LVEF, left ventricular ejection fraction; MGP, matrix Gla protein; MSCT, multislice computed tomography; N/A, not applicable; NYHA, New York Heart Association; PCSK9, proprotein convertase subtilisin/kexin type 9; PET, positron emission tomography; RANKL, receptor activator of NF-κB ligand; VKA, vitamin K antagonist; VO_2max, maximum oxygen consumption.