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Update - Week 51, 2018
Curated by Peter Lansberg,
a Dutch lipidologist and educator, and
reviewed by prof. Philip Barter, Past President of the
International Atherosclerosis Society.

The IAS Statin Newsletter will keep you up-to-date with all recent statin publications, using a curated approach to select relevant articles.

Key publications

Atorvastatin rapidly reduce carotid plaque neovascularization
By using new imaging techniques to observe carotid plaque changes the authors examined the effects of atorvastatin on Chinese post ischemic stroke patients. From 117 patients that presented with an acute ischemic stroke in a single institution (June 2018 – February 2018), 86 were selected for further evaluation. Ultrasound imaging was performed and grayscale as well as superior microvascular imaging (SMI) and contrast enhance ultrasound sagittal images (CEUS) were acquired. Patients received 20 mg atorvastatin or placebo for 6 months and were evaluated at baseline and after 6 months. No significant differences could be discerned at baseline but after 6 months, patients treated with atorvastatin 20 mg showed marked reductions of total cholesterol, LDL-c and triglycerides. Both SMI and CEUS techniques revealed reduced intraplaque neovascularization’s 69.23% to 48.72% and 74.1% to 69.23% respectively. When Compared both techniques were markedly congruent: 0.75 (P<0.001). Patient allocated to the placebo group showed similar outcomes at baseline and after 6 months 65.12% to 67.44% for SMI and 74.41% to 74.41% for CEUS. The authors concluded that 6 months of atorvastatin 20 mg therapy reduced intraplaque neovascularization significantly and SMI performed on par with CEUS but is a safer and cheaper ultrasonographic technique that can be used to identify carotid plaque instability.
Zhu YC, Jiang XZ, Bai QK et al. Evaluating the Efficacy of Atorvastatin on Patients with Carotid Plaque by an Innovative Ultrasonography. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30563776
Updated meta-analysis on high dose statin pre-PCI
In this updated met-analysis of 15 randomized trials high dose statin pre-treatment improved final TIMI flow grade. In total 4240 patients were included in the selected 15 trials, 7 studies evaluated atorvastatin 80 mg, 7 trials rosuvastatin (3 using 20 mg and 4 using 40 mg) and 1 study was done with simvastatin 80 mg. High dose statin pre-PCI significantly improved final TIMI flow grade compared to the control group, OR 0.61 (0.46-0.80, p=0.0005)  After 1 month – 1 year of high dose statin treatment MACE were reduced by 48% When comparing high dose with moderate dose statins the incidence of MACE was reduced by 14.1% and 8.8% (p=0.018) respectively. No significant difference were observed in patients with stable angina. The authors pointed out that the timing of preloading was critical, in ACS patients, with a narrow therapeutic window of approximately 2 hrs. to reduce reperfusion injury and improving clinical outcomes. The authors concluded that high dose statin pre-PCI had a significant effect on post procedure myocardial perfusion, by improving TIMI flow, as well as reducing MACE, particularly in statin naïve and STEMI patents.
Xiao Y, He S, Zhang Z et al. Effect of High-Dose Statin Pretreatment for Myocardial Perfusion in Patients Receiving Percutaneous Coronary Intervention (PCI): A Meta-Analysis of 15 Randomized Studies. Medical science monitor : international medical journal of experimental and clinical research 2018; 24:9166-9176. http://www.ncbi.nlm.nih.gov/pubmed/?term=30557296
First Meta-analysis on anti-inflammatory properties of statins in MS
The two driving forces of atherosclerosis are lipids and inflammation. Statins address both, although the latter is still debated by some. In this meta-analysis statin anti-inflammatory effects in patients with metabolic syndrome (MS) were evaluated. MS patients are characterized by increased inflammatory markers in the plasma. The authors collected the published data of 113 RCT’s, that included 19 644 patients. The biomarkers studied in these trials and this meta-analysis were: hsCRP, TNF alpha, Il1 and IL6. Statin use in MS patients significantly reduce  hsCRP, SMD= -0.97 (-1.10, -0.85; P<0.001; I2: 95.1 %); TNFalpha SMD -1.88 (-2.40, -1.38; P<0.001; I2: 97.2 %); IL-6, SMD= -1.67 9 -1.98, -1.34; P<0.001; I2: 96.5 %); and IL-1 concentrations, SMD= -8.35 (-10.49, -6.22; P<0.001; I2: 98.4 %). The unequivocal anti-inflammatory effects of statins were confirmed in this meta-analysis, differences between statins and statin dosages could not be discerned from the collected data.
Tabrizi R, Tamtaji OR, Mirhosseini N et al. The effects of statin use on inflammatory markers among patients with metabolic syndrome and related disorders: A systematic review and meta-analysis of randomized controlled trials. Pharmacol Res 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30576798
Tabrizi R, Tamtaji OR, Mirhosseini N et al. The effects of statin use on inflammatory markers among patients with metabolic syndrome and related disorders: A systematic review and meta-analysis of randomized controlled trials. Pharmacol Res 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30576798
Rosuvastatin 40 mg improves plaque stability of non-culprit vessels in post-STEMI patients
In this observational study, 103 STEMI patients underwent an IVUS and OCT analysis on 2 of their non-infarct related arteries. The aim was to visualize the intrinsic vascular effects of statins by optical coherence tomography (OCT). Patients received rosuvastatin 20 for two weeks and continued with rosuvastatin 40 for the remaining study period of 13 months. Primary end points of the study were change in minimum fibrous cap thickness (FCT) and change in macrophage line arc. Secondary endpoints included change in mean FCT, lipid pool arc, and plaque type by OCT. Exploratory endpoints included macrophage dots. Serial OCT images were evaluable in 153 arteries of 83 patients. After study completion LDL-c was reduced from 128 mg/dl to 73.6 mg/dl. Minimum FCT (31 lesions/27 patients), increased from 64.9 ± 19.9 mm to 87.9 ± 38.1 mm (p = 0.008). Macrophage line arc decreased from 9.60 ± 12.80 to 6.460 ± 9.60 (p < 0.0001). The secondary endpoint, mean lipid arc, decreased from 55.90 ± 370 to 43.50 ± 33.50. In lesion-level analyses (n = 191), 9 of 13 thin-cap fibroatheromas (TCFAs) at baseline (69.2%) regressed to non-TCFA morphology, whereas 2 of 178 non-TCFA lesions (1.1%) progressed to TCFAs. The authors concluded that, within the limits of the observational nature of this study, 40 mg of Rosuvastatin was associated with markedly improved vascular OCT imaging characteristic of non-culprit vessels in post-STEMI patients. To confirm these observations, replication studies are warranted in order to re-assess if measuring OCT-defined coronary atheroma composition is clinically relevant and can be used as a follow-up evaluation to determine statin efficacy on promoting plaque stability.
Raber L, Koskinas KC, Yamaji K et al. Changes in Coronary Plaque Composition in Patients With Acute Myocardial Infarction Treated With High-Intensity Statin Therapy (IBIS-4): A Serial Optical Coherence Tomography Study. JACC. Cardiovascular imaging 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30553686
Rosuvastatin for VTE prophylaxis?
In earlier statin trials, signals of reduced risk for venous thromboembolism (VTE) surfaced, but have never been fully explored. The risk for first VTE were 14-54% lower and recurrent VTE risk was reduced by 27% in patients that used statins. In this study patients with a history of VTE were included in a placebo controlled randomized 4-week trial. The aim was to establish if rosuvastatin 20 mg would prevent VTE events without increasing bleeding risk. Patients were asked to stop using anticoagulants 1 month prior to the start of the trials to observe relevant changes in their coagulation profile. Thrombin generation assay (TGA) was used to evaluate the anti-coagulant effects of statins. Because endogenous thrombin potential (ETP) and thrombin peak are validated markers for VTE risk, they were chosen as primary endpoints of this study. Of the 255 patients 245 completed the study; 126 were taking rosuvastatin and 119 were allocated to a placebo. An ETP increase of 7.8% was associated with placebo use and a 1.9% decrease in patients using rosuvastatin. The mean difference between treatments was calculated as 10.4% (4.5-16.2%). Thrombin peak increased in both treatment arms, but this was more pronounced in the placebo users, 7.6% vs 2.9% in the rosuvastatin group. Comparing the two treatment arms resulted in percentage thrombin peak difference of 5% (-0.2-10.2%). The observed changes associated with rosuvastatin were more pronounced in patients with CV risk factors and unprovoked VTE. This study corroborate earlier observations that statins affect coagulation and thrombin generation. The authors suggest that their finding provide the clinical rationale to conduct a large randomized controlled trial to evaluate the effectiveness of rosuvastatin to decrease risk of recurrent VTE complications. 
Orsi FA, Biedermann JS, Kruip M et al. Rosuvastatin use reduces thrombin generation potential in patients with venous thromboembolism: a randomized controlled trial. Journal of thrombosis and haemostasis : JTH 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30565854

Relevant publications
  1. Takata K, Nicholls SJ. Tackling Residual Atherosclerotic Risk in Statin-Treated Adults: Focus on Emerging Drugs. Am J Cardiovasc Drugs 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30565156
  2. Shirahama R, Ono T, Nagamatsu S et al. Coronary Artery Plaque Regression by a PCSK9 Antibody and Rosuvastatin in Double-heterozygous Familial Hypercholesterolemia with an LDL Receptor Mutation and a PCSK9 V4I Mutation. Intern Med 2018; 57:3551-3557. http://www.ncbi.nlm.nih.gov/pubmed/?term=30555118
  3. Schultz NEO, Hasseldam H, Rasmussen RS et al. Statin treatment before stroke reduces pro-inflammatory cytokine levels after stroke. Neurol Res 2018:1-9. http://www.ncbi.nlm.nih.gov/pubmed/?term=30574850
  4. Ahmed O, Littmann K, Gustafsson U et al. Ezetimibe in Combination With Simvastatin Reduces Remnant Cholesterol Without Affecting Biliary Lipid Concentrations in Gallstone Patients. J Am Heart Assoc 2018; 7:e009876. http://www.ncbi.nlm.nih.gov/pubmed/?term=30561264
  5. Kinsey TL, Sturmer T, Poole C et al. Changing predictors of statin initiation in US women over two decades. Pharmacoepidemiol Drug Saf 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30565779
  6. Kamal AK, Khalid W, Muqeet A et al. Making prescriptions "talk" to stroke and heart attack survivors to improve adherence: Results of a randomized clinical trial (The Talking Rx Study). PLoS One 2018; 13:e0197671. http://www.ncbi.nlm.nih.gov/pubmed/?term=30571697
  7. Kakadiaris IA, Vrigkas M, Yen AA et al. Machine Learning Outperforms ACC / AHA CVD Risk Calculator in MESA. J Am Heart Assoc 2018; 7:e009476. http://www.ncbi.nlm.nih.gov/pubmed/?term=30571498
  8. Johns I, Moschonas KE, Medina J et al. Risk classification in primary prevention of CVD according to QRISK2 and JBS3 'heart age', and prevalence of elevated high-sensitivity C reactive protein in the UK cohort of the EURIKA study. Open heart 2018; 5:e000849. http://www.ncbi.nlm.nih.gov/pubmed/?term=30564373
  9. Hines DM, Rane P, Patel J et al. Treatment patterns and patient characteristics among early initiators of PCSK9 inhibitors. Vasc Health Risk Manag 2018; 14:409-418. http://www.ncbi.nlm.nih.gov/pubmed/?term=30573963
  10. Grundy SM, Stone NJ, Bailey AL et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: Executive Summary. Circulation 2018:Cir0000000000000624. http://www.ncbi.nlm.nih.gov/pubmed/?term=30565953
  11. Farooqi MAM, Malhotra N, Mukherjee SD et al. Statin therapy in the treatment of active cancer: A systematic review and meta-analysis of randomized controlled trials. PLoS One 2018; 13:e0209486. http://www.ncbi.nlm.nih.gov/pubmed/?term=30571754
  12. Du Y, Wang S, Chen Z et al. Association of SLCO1B1 polymorphisms and atorvastatin safety and efficacy: A meta-analysis. Current pharmaceutical design 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30569848
  13. Choi HD, Chae SM. Comparison of efficacy and safety of combination therapy with statins and omega-3 fatty acids versus statin monotherapy in patients with dyslipidemia: A systematic review and meta-analysis. Medicine (Baltimore) 2018; 97:e13593. http://www.ncbi.nlm.nih.gov/pubmed/?term=30558030
  14. Zeng H, Li Z, He G et al. Use of statins and the risk of delirium in critically ill and surgical patients: Protocol of a systematic review and meta-analysis. Medicine (Baltimore) 2018; 97:e13679. http://www.ncbi.nlm.nih.gov/pubmed/?term=30572490
  15. Yeager R, Riggs DW, DeJarnett N et al. Association Between Residential Greenness and Cardiovascular Disease Risk. J Am Heart Assoc 2018; 7:e009117. http://www.ncbi.nlm.nih.gov/pubmed/?term=30561265
  16. Shyamsundar M, O'Kane C, Perkins GD et al. Prevention of post-operative complications by using a HMG-CoA reductase inhibitor in patients undergoing one-lung ventilation for non-cardiac surgery: study protocol for a randomised controlled trial. Trials 2018; 19:690. http://www.ncbi.nlm.nih.gov/pubmed/?term=30563555
  17. Schultz JL, Nopoulos PC, Killoran A, Kamholz JA. Statin use and delayed onset of Huntington's disease. Movement disorders : official journal of the Movement Disorder Society 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30576007
  18. Pantea M, Negovan A, Voidazan S et al. Statins and gastroduodenal endoscopic lesions: A case-control study. Medicine (Baltimore) 2018; 97:e13579. http://www.ncbi.nlm.nih.gov/pubmed/?term=30558024
  19. Klein R, Lee KE, Tsai MY et al. Oxidized Low-Density Lipoprotein and the Incidence of Age-related Macular Degeneration. Ophthalmology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30572074
  20. Jia L, Wang L, Liu W et al. Erratum: Fluvastatin inhibits cardiomyocyte apoptosis after myocardial infarction through Toll pathway. Experimental and therapeutic medicine 2018; 16:5424. http://www.ncbi.nlm.nih.gov/pubmed/?term=30555540
  21. Gosho M. Rhabdomyolysis risk from the use of two-drug combination of antidyslipidemic drugs with antihypertensive and antidiabetic medications: a signal detection analysis. Fundamental & clinical pharmacology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30575126

Miscellaneous publications
  1. Yuan X, Zhang M, Wang Y et al. Using Co-Axial Electrospray Deposition to Eliminate Burst Release of Simvastatin From Microparticles and to Enhance Induced Osteogenesis. Journal of biomaterials science. Polymer edition 2018:1-37. http://www.ncbi.nlm.nih.gov/pubmed/?term=30572791
  2. Xu HY, Xue JX, Gao H et al. Fluvastatin-mediated down-regulation of SATB1 affects aggressive phenotypes of human non-small-cell lung cancer cell line H292. Life sciences 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30557545
  3. Sokalska A, Hawkins AB, Yamaguchi T, Duleba AJ. Lipophilic statins inhibit growth and reduce invasiveness of human endometrial stromal cells. Journal of assisted reproduction and genetics 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30554393
  4. Sato T, Arakawa M, Tashima Y et al. Statins Reduce Thoracic Aortic Aneurysm Growth in Marfan Syndrome Mice via Inhibition of the Ras-Induced ERK (Extracellular Signal-Regulated Kinase) Signaling Pathway. J Am Heart Assoc 2018; 7:e008543. http://www.ncbi.nlm.nih.gov/pubmed/?term=30571378
  5. Mansouri E, Assarehzadegan MA, Nejad-Dehbashi F, Kooti W. Effects of Pravastatin in Adriamycin-Induced Nephropathy in Rats. Iranian journal of pharmaceutical research : IJPR 2018; 17:1413-1419. http://www.ncbi.nlm.nih.gov/pubmed/?term=30568699
  6. Kogawa AC, Pires A, Salgado HRN. Atorvastatin: A Review of Analytical Methods for Pharmaceutical Quality Control and Monitoring. J AOAC Int 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30563586
  7. Gonen A, Choi SH, Miu P et al. A monoclonal antibody to assess oxidized cholesteryl esters associated with apoAI and apoB-100 lipoproteins in human plasma. Journal of lipid research 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30563909
  8. Abdeen A, Aboubakr M, Elgazzar D et al. Rosuvastatin attenuates piroxicam-mediated gastric ulceration and hepato-renal toxicity in rats. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 2018; 110:895-905. http://www.ncbi.nlm.nih.gov/pubmed/?term=30572194
  9. Wang CZ, Wang YH, Lin CW et al. Combination of a Bioceramic Scaffold and Simvastatin Nanoparticles as a Synthetic Alternative to Autologous Bone Grafting. Int J Mol Sci 2018; 19. http://www.ncbi.nlm.nih.gov/pubmed/?term=30567319
  10. Mehanna MM, Shabarek MI, El-Maradni HA. Spray-Dried pH Sensitive Microparticles: Effectual Methodology to Ameliorate the Bioavailability of Acid Labile Pravastatin. Drug development and industrial pharmacy 2018:1. http://www.ncbi.nlm.nih.gov/pubmed/?term=30575415

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