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      Association of Statin Use and Mortality After Transcatheter Aortic Valve Replacement

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          Abstract

          Background

          Statins may reduce mortality after transcatheter aortic valve replacement (TAVR) through prevention of atherosclerotic events or pleiotropic effects. However, the competing mortality risks in TAVR patients may dilute any positive effect of statins. We sought to understand the association of statin use with post‐TAVR mortality.

          Methods and Results

          We included high– or intermediate–surgical risk patients who underwent TAVR as a part of the PARTNER (Placement of Aortic Transcatheter Valves) II and Sapien 3 trials and registries. Outcomes included 2‐year all‐cause, cardiovascular, and noncardiovascular mortality. We used propensity score matching to generate matched pairs between those discharged on a statin and those not on a statin after TAVR. Bias was explored with falsification end points (urinary infection, hip fracture). Among 3956 patients who underwent TAVR, we matched 626 patients on a statin with 626 patients not on a statin at discharge. Among matched patients, statin use was associated with lower risk of all‐cause (hazard ratio [HR] 0.65, 95% CI 0.49‐0.87, P=0.001), cardiovascular (HR 0.66, 95% CI 0.46‐0.96, P=0.030), and noncardiovascular mortality (HR 0.64, 95% CI 0.44‐0.99, P=0.045) compared with no statin use. The survival curves diverged within 3 months and continued to separate over a median follow‐up of 2.1 years. The falsification end points were similar among groups (urinary infection, P=0.66; hip fracture, P=0.64).

          Conclusions

          In an observational, propensity‐matched analysis of TAVR patients, statin use was associated with lower rates of cardiovascular and noncardiovascular mortality compared with no statin use. Given the early emergence of the apparent protective effect of statins, this result may be driven either by pleiotropic effects or by residual confounding despite propensity‐matching methodology.

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          Most cited references20

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          2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults

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            Kruppel-like factor 2 as a novel mediator of statin effects in endothelial cells.

            Although 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are known to modulate endothelial function, the transcriptional mechanisms underlying these effects are incompletely understood. We hypothesized that Lung-Kruppel-like factor (LKLF/KLF2), a novel and potent regulator of endothelial gene expression, may mediate the downstream effects of statins. Here we report that statin-induced expression of endothelial NO synthase (eNOS) and thrombomodulin is KLF2 dependent. KLF2 mRNA was induced by treatment with multiple statins in a concentration-dependent manner. Multiple lines of evidence suggest that this induction is dependent on inhibition of the Rho pathway and requires de novo transcription. Furthermore, promoter deletion and mutational analyses suggest that mevastatin induced KLF2 promoter activity through a single myocyte enhancer factor binding site. Finally, small-interfering RNA-mediated knockdown of KLF2 strongly attenuated the ability of mevastatin to increase eNOS and thrombomodulin accumulation in endothelial cells. Taken together, these observations indicate that statin-dependent induction of eNOS and thrombomodulin requires KLF2 and thereby provides a novel molecular target for modulating endothelial function in vascular disease.
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              Randomized trial of the effects of cholesterol-lowering with simvastatin on peripheral vascular and other major vascular outcomes in 20,536 people with peripheral arterial disease and other high-risk conditions.

              (2007)
              The Heart Protection Study (HPS) provides an opportunity to assess directly the effects of cholesterol-lowering therapy on major vascular events (defined as myocardial infarction, coronary death, stroke, or revascularization) in patients with peripheral arterial disease (PAD). In addition, the effects on peripheral vascular events (ie, non-coronary revascularization, aneurysm repairs, major amputations or PAD deaths) can be assessed. 6748 UK adults with PAD and 13,788 other high-risk participants were randomly allocated to receive 40 mg simvastatin daily or matching placebo, yielding an average LDL cholesterol difference of 1.0 mmol/L (39 mg/dL) during a mean of 5 years. For participants with PAD, allocation to simvastatin was associated with a highly significant 22% (95% CI 15-29) relative reduction in the rate of first major vascular event following randomisation (895 [26.4%] simvastatin-allocated vs 1101 [32.7%] placebo-allocated; P < .0001), which was similar to that seen among the other high-risk participants. The absolute reduction in first major vascular event was 63 (SE 11) per 1000 patients with PAD and 50 (SE 7) per 1000 without pre-existing PAD. Overall, among all participants, there was a 16% (5-25) relative reduction in the rate of first peripheral vascular event following randomisation (479 [4.7%] simvastatin vs 561 [5.5%] placebo), largely irrespective of baseline LDL cholesterol and other factors. This effect chiefly reflects a 20% (8-31) relative reduction in non-coronary revascularization procedures (334 [3.3%] vs 415 [4.0%]; P = .002). HPS demonstrates the benefits of cholesterol-lowering statin therapy in patients with PAD, regardless of their presenting cholesterol levels and other presenting features. Allocation to 40 mg simvastatin daily reduces the rate of first major vascular events by about one-quarter, and that of peripheral vascular events by about one-sixth, with large absolute benefits seen in participants with PAD because of their high vascular risk. Consequently, statin therapy should be considered routinely for all patients with PAD.
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                Author and article information

                Contributors
                periokonnyp@umkc.edu
                Journal
                J Am Heart Assoc
                J Am Heart Assoc
                10.1002/(ISSN)2047-9980
                JAH3
                ahaoa
                Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
                John Wiley and Sons Inc. (Hoboken )
                2047-9980
                05 April 2019
                16 April 2019
                : 8
                : 8 ( doiID: 10.1002/jah3.2019.8.issue-8 )
                : e011529
                Affiliations
                [ 1 ] Saint Luke's Mid America Heart Institute/University of Missouri Kansas City Kansas City MO
                [ 2 ] Cardiovascular Research Foundation New York NY
                [ 3 ] Northwestern University Feinberg School of Medicine Chicago IL
                [ 4 ] Cleveland Clinic Cleveland OH
                [ 5 ] Medstar Heart and Vascular Institute and Georgetown University Washington DC
                [ 6 ] Columbia University Medical Center New York‐Presbyterian Hospital New York NY
                [ 7 ] BC Centre for Improved Cardiovascular Health Vancouver BC Canada
                Author notes
                [*] [* ] Correspondence to: Poghni A. Peri‐Okonny, MD, Department of Cardiovascular Medicine, Saint Luke's Mid America Heart Institute, 4401 Wornall Road, CV Research 9th Floor, Kansas City, MO 64111. E‐mail: periokonnyp@ 123456umkc.edu
                Article
                JAH33979
                10.1161/JAHA.118.011529
                6507186
                30947591
                d4287090-230b-4d09-923b-27e1c6521e92
                © 2019 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                : 16 November 2018
                : 22 February 2019
                Page count
                Figures: 6, Tables: 4, Pages: 12, Words: 7497
                Funding
                Funded by: Edwards Lifesciences
                Funded by: National Heart, Lung, and Blood Institute
                Award ID: T32 HL110837
                Award ID: K23 HL116799
                Categories
                Original Research
                Original Research
                Valvular Heart Disease
                Custom metadata
                2.0
                jah33979
                16 April 2019
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.6.2.1 mode:remove_FC converted:16.04.2019

                Cardiovascular Medicine
                aortic stenosis,outcome,statin therapy,transcutaneous aortic valve implantation,aortic valve replacement/transcather aortic valve implantation

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