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      Effect of Denosumab or Alendronic Acid on the Progression of Aortic Stenosis : A Double-Blind Randomized Controlled Trial

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      , MD 1 , * , , MD 1 , * , , MBBS 1 , * , 1 , , PhD 2 , , MSc 3 , , MSc 3 , , MD 1 , , MD 4 , , PhD 4 , , MBChB 1 , 6 , , MD 1 , , MD 1 , , MD 1 , , MD 1 , , PhD 1 , , PhD 4 , , MBChB 7 , , MD 5 , , MD 1 , , MD 8 , , MD 1 , , MD 1 ,
      Circulation
      Lippincott Williams & Wilkins
      alendronate, aortic stenosis, computed tomography, X-ray, calcium signaling, denosumab

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          Abstract

          Supplemental Digital Content is available in the text.

          Background:

          Valvular calcification is central to the pathogenesis and progression of aortic stenosis, with preclinical and observational studies suggesting that bone turnover and osteoblastic differentiation of valvular interstitial cells are important contributory mechanisms. We aimed to establish whether inhibition of these pathways with denosumab or alendronic acid could reduce disease progression in aortic stenosis.

          Methods:

          In a single-center, parallel group, double-blind randomized controlled trial, patients >50 years of age with calcific aortic stenosis (peak aortic jet velocity >2.5 m/s) were randomized 2:1:2:1 to denosumab (60 mg every 6 months), placebo injection, alendronic acid (70 mg once weekly), or placebo capsule. Participants underwent serial assessments with Doppler echocardiography, computed tomography aortic valve calcium scoring, and 18F-sodium fluoride positron emission tomography and computed tomography. The primary end point was the calculated 24-month change in aortic valve calcium score.

          Results:

          A total of 150 patients (mean age, 72±8 years; 21% women) with calcific aortic stenosis (peak aortic jet velocity, 3.36 m/s [2.93–3.82 m/s]; aortic valve calcium score, 1152 AU [655–2065 AU]) were randomized and received the allocated trial intervention: denosumab (n=49), alendronic acid (n=51), and placebo (injection n=25, capsule n=25; pooled for analysis). Serum C-terminal telopeptide, a measure of bone turnover, halved from baseline to 6 months with denosumab (0.23 [0.18–0.33 µg/L] to 0.11 µg/L [0.08–0.17 µg/L]) and alendronic acid (0.20 [0.14–0.28 µg/L] to 0.09 µg/L [0.08–0.13 µg/L]) but was unchanged with placebo (0.23 [0.17–0.30 µg/L] to 0.26 µg/L [0.16–0.31 µg/L]). There were no differences in 24-month change in aortic valve calcium score between denosumab and placebo (343 [198–804 AU] versus 354 AU [76–675 AU]; P=0.41) or alendronic acid and placebo (326 [138–813 AU] versus 354 AU [76–675 AU]; P=0.49). Similarly, there were no differences in change in peak aortic jet velocity or 18F-sodium fluoride aortic valve uptake.

          Conclusions:

          Neither denosumab nor alendronic acid affected progression of aortic valve calcification in patients with calcific aortic stenosis. Alternative pathways and mechanisms need to be explored to identify disease-modifying therapies for the growing population of patients with this potentially fatal condition.

          Registration:

          URL: https://www.clinicaltrials.gov; Unique identifier: NCT02132026.

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          Most cited references38

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          2017 ESC/EACTS Guidelines for the management of valvular heart disease.

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            2020 ACC/AHA Guideline for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines

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              Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis.

              Hyperlipidemia has been suggested as a risk factor for stenosis of the aortic valve, but lipid-lowering studies have had conflicting results. We conducted a randomized, double-blind trial involving 1873 patients with mild-to-moderate, asymptomatic aortic stenosis. The patients received either 40 mg of simvastatin plus 10 mg of ezetimibe or placebo daily. The primary outcome was a composite of major cardiovascular events, including death from cardiovascular causes, aortic-valve replacement, nonfatal myocardial infarction, hospitalization for unstable angina pectoris, heart failure, coronary-artery bypass grafting, percutaneous coronary intervention, and nonhemorrhagic stroke. Secondary outcomes were events related to aortic-valve stenosis and ischemic cardiovascular events. During a median follow-up of 52.2 months, the primary outcome occurred in 333 patients (35.3%) in the simvastatin-ezetimibe group and in 355 patients (38.2%) in the placebo group (hazard ratio in the simvastatin-ezetimibe group, 0.96; 95% confidence interval [CI], 0.83 to 1.12; P=0.59). Aortic-valve replacement was performed in 267 patients (28.3%) in the simvastatin-ezetimibe group and in 278 patients (29.9%) in the placebo group (hazard ratio, 1.00; 95% CI, 0.84 to 1.18; P=0.97). Fewer patients had ischemic cardiovascular events in the simvastatin-ezetimibe group (148 patients) than in the placebo group (187 patients) (hazard ratio, 0.78; 95% CI, 0.63 to 0.97; P=0.02), mainly because of the smaller number of patients who underwent coronary-artery bypass grafting. Cancer occurred more frequently in the simvastatin-ezetimibe group (105 vs. 70, P=0.01). Simvastatin and ezetimibe did not reduce the composite outcome of combined aortic-valve events and ischemic events in patients with aortic stenosis. Such therapy reduced the incidence of ischemic cardiovascular events but not events related to aortic-valve stenosis. (ClinicalTrials.gov number, NCT00092677.) 2008 Massachusetts Medical Society
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                Author and article information

                Journal
                Circulation
                Circulation
                CIR
                Circulation
                Lippincott Williams & Wilkins (Hagerstown, MD )
                0009-7322
                1524-4539
                29 April 2021
                22 June 2021
                : 143
                : 25
                : 2418-2427
                Affiliations
                [1 ]British Heart Foundation Centre for Cardiovascular Science (T.A.P., M.K.D., R.B., A.C.W., M.C.W., P.D.A., J.P.M.A., T.R.G.C., W.S.A.J., M.S., T.F., N.B., D.E.N., M.R.D.), University of Edinburgh, United Kingdom.
                [2 ]Edinburgh Clinical Trials Unit (L.F.), University of Edinburgh, United Kingdom.
                [3 ]Edinburgh Clinical Research Facility (E.E., C.G.), University of Edinburgh, United Kingdom.
                [4 ]Edinburgh Imaging (E.J.R.v.B., A.F., C.L.), University of Edinburgh, United Kingdom.
                [5 ]Institute of Genetics and Molecular Medicine (S.H.R.), University of Edinburgh, United Kingdom.
                [6 ]Christchurch Heart Institute, University of Otago, New Zealand (P.D.A.).
                [7 ]Norwich Medical School, University of East Anglia, United Kingdom (W.F.).
                [8 ]King’s College London, United Kingdom (B.P.).
                Author notes
                Correspondence to: Marc R. Dweck, MD, British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, United Kingdom. Email marc.dweck@ 123456ed.ac.uk
                Article
                00002
                10.1161/CIRCULATIONAHA.121.053708
                8212878
                33913339
                6bfe9e63-c4ad-4046-ae63-d9d811d394b7
                © 2021 The Authors.

                Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.

                This article is made available via the PMC Open Access Subset for unrestricted re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections.

                History
                : 12 January 2021
                : 2 April 2021
                Categories
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                alendronate,aortic stenosis,computed tomography, x-ray,calcium signaling,denosumab

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