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Update - Week 48, 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

Cochrane meta-analysis on Ezetimibe
Using the Cochrane Handbook for Systematic Reviews of Interventions and the GRADE to assess the quality of evidence, the authors of this Cochrane analysis set out to evaluate the efficacy and safety of ezetimibe for the prevention of CVD and all-cause mortality. The CENTRAL, MEDLINE, Embase and Web of Science literature collection as well as two clinical trial registry platforms were queried for RCTs in which ezetimibe was evaluated either against placebo or alternative lipid lowering medications e.g. statins and fibrates. Participants had to be adults and diagnosed with or without ASCVD. Minimum required follow up time was 12 months. In all 26 trials (N=23 499) were used for the final analysis. By far the trial that supplied the greatest weight in this analysis was the IMPROVE IT, in contributed 41.5% - 98% of the weight in the different meta-analysis. Major CV events were reduced modestly when ezetimibe was combined with a statin and compared to statin mono therapy; RR 0.94 (0.9-0.98). These conclusions were based on 10 trials with moderate quality evidence. Total mortality did not show relevant improvement when ezetimibe was added to a statin or to a fibrate. RR 0.98 (0.91 – 1.05). This conclusion was based on 8 high quality studies. For non-fatal MI and stroke, benefits were observed RR: 0.88 (0.81 – 0.91) and RR: 0.83 (0.71 – 0.97) respectively, for both 6 moderate quality studies were used in the analysis. No improved outcomes for re-vascularization and/or CV mortality could be discerned. For the latter, based on 6 moderate quality studies, a RR of 1.0 (0.89-1.12) was noted. No safety signal surfaced for hepatic and/or muscle abnormalities, however the respectively 4 and trials that reported on these safety parameters safety were of low quality. The authors concluded that moderate – high quality evidence supports the use of ezetimibe as add-on lipid lowering treatment to statins, but only in a secondary/ACS patient population and with at best a modest effect on non-fatal MACE and cerebral vascular events only. There was insufficient data to evaluate the benefits/harms of ezetimibe mono-therapy and the use of ezetimibe in a primary prevention setting.
Zhan S, Tang M, Liu F et al. Ezetimibe for the prevention of cardiovascular disease and all-cause mortality events. The Cochrane database of systematic reviews 2018; 11:Cd012502. http://www.ncbi.nlm.nih.gov/pubmed/?term=30480766
The ultimate CVD risk assessment – simple and reliable
Determining which patients need to be treated with statins and in whom lipid lowering interventions are unnecessary is possible by calculating the CVD risk of primary prevention patients. Over the years the number of risk scores have increased and debates on the quality of the individual risk scores has created confusion amongst the health care providers when determining which of the different scoring systems to use for their patients. In this laudable ESC initiative, the aim was to compare the precision of 4 well accepted risk scoring systems: Framingham Score (FRS), Pooled Cohort Risk Equation (PCE). Reynolds Risk Score (RRS) and the ESC/EAS SCORE charts and recalibrate the different scoring system using collected data of 86 prospective studies and >360 000 participants from 22 countries. The clinical implications of prescribing statins to individuals with a “high” 10-year risk for ASCVD events were determined. Recalibration of the scores was achieved by using risk factor profiles of the individual participants and corelate the predicted risk to the observed incidence of CHD in the targeted populations. The FRS, SCORE and PCE overestimated CVD risk by respectively 10%, 52% and 41%. The RRS under-predicted the risk by 10%. When using the original version, 29%-39% of the >40 years old would be classified as high-risk. After calibration this was reduced 22%-24%. The authors concluded that traditional CVD risk algorithms showed substantial variations in their risk predictions, by a simple recalibration method the performance of these different tools were equalized, and their predictive accuracy significantly improved.  
Pennells L, Kaptoge S, Wood A et al. Equalization of four cardiovascular risk algorithms after systematic recalibration: individual-participant meta-analysis of 86 prospective studies. Eur Heart J 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30476079
High dose atorvastatin in Chinese post ischemic stroke patients
The use of statin in post-stroke patients has evolved into a standard and guideline recommended approach. Controversy still exists regarding the benefits vs harms in hemorrhagic stroke patients and the spectrum of protective effects in both ischemic and hemorrhagic stroke victims. In this study the authors investigated the effects of atorvastatin high dose (60 mg) vs low dose (20 mg) on micro emboli in post-acute stroke patients visualized by using a transcranial Doppler imaging. Patients admitted for an acute stroke were randomized to atorvastatin 20 or 60 mg <72 hr. of symptom onset. Patients that started with high dose were down titrated to 20 mg after 7 days. Imaging for micro emboli was performed at day 1 (pre-treatment), day 3 and day 7. Measurements of metalloproteinase-9 (MMP-9), hsCRP and NIHSS score assessments were executed at day 1 and 7. No differences in micro emboli were observed on day 1 between the two treatment arms, 25 (58.3%) and 30 (52.6%) in the intensive statin (n = 60) and control (n = 57) groups, respectively (p = 0.342). The patients using atorvastatin 60 mg experienced fewer micro emboli (n = 9; 15.0%) compared with controls (n = 16; 28.1%; p = 0.002). MMP-9 and hs-CRP levels were similar on day 1, but lower levels were observed in the intensive treated patients on day 7; MMP-9, median 79.3 vs. 95.9 μg/L (p = 0.004) and hs-CRP median 2.01 vs. 3.60 mg/L (p = 0.020). NIHSS scores on days 1 and 7 and the modified Rankin Scale on day 90 were comparable in both treatment arms. Based on these results the authors concluded that using atorvastatin 60 mg vs 20 mg showed improved outcomes in micro emboli occurrences as well as lower plasma levels of hs CRP and MMP-9 without adverse events. Using atorvastatin 60 mg in Chinese post-acute ischemic stroke patients can improve therapeutic efficacy, but the observed results need to be confirmed by larger randomized control studies.  
Chen X, Zhuang X, Peng Z et al. Intensive Statin Therapy for Acute Ischemic Stroke to Reduce the Number of Microemboli: A Preliminary, Randomized Controlled Study. European neurology 2018; 80:163-170. http://www.ncbi.nlm.nih.gov/pubmed/?term=30485853
Reduced mortality and no increased bleeding in post ICH patients on statins
The risk of increased bleeding in patients prescribed a statin after a hemorrhagic stroke remains an elusive complication and might be not as clinically relevant as shown in this Swedish real life retrospective observational study. Using data collected of 6082 intra cerebral hemorrhage (ICH) patients (2004 – 2009), patient using a statin at discharge, were propensity score matched with no-statin using controls. Statins were used by 1097 (18%) of the ICH patients. During a 3.1-year median follow-up 1434 (22.6%) deaths and 234 (3.8%) recurrent ICH occurred. The use of statins was associated with a reduce risk of death, HR 0.82 (0.60-0.84) but reassuringly not with an increased or decreased bleeding risk; risk recurrent ICH 0.82 (0.55-1.22).
The results of this, although observational by nature, confirm earlier observations that using statin is associated with improved outcomes and does not enhance bleeding recurrences in post ICH patients.  
Asberg S, Farahmand B, Henriksson KM, Appelros P. Statins as secondary preventives in patients with intracerebral hemorrhage. Int J Stroke 2018:1747493018816476. http://www.ncbi.nlm.nih.gov/pubmed/?term=30484749
Patients not treated according to their 10-years ASCVD risk prior to first ACS event
The price patients pay for not being adequately protected prior to ASCVD events was revealed in this study. Using the 2013 ACC/AHA guidelines for cholesterol management, the authors retrospectively evaluated how patient were managed, in a primary prevention setting, prior to their index ASCVD event.  The 10-year predicted ASCVD risk was re-calculated for 1 265 ACS patients, free of CVD and aged 40-75 years. Patients were then evaluated for use of the right statin in the right dose prior to the ACS event. Of statin eligible patients only 1:5 was prescribed the appropriate statin. Despite the guideline dictated recommendation to increase statin dosage/intensity in patients ≥7.5% vs 5.0% – 7.5% ASCVD risk, the observed differences were marginal. A sobering observation was that even when patients would have been prescribed the right statin based on their elevated ASCVD risk, a significant number would have been missed. Of the STEMI patients 30% had and ASCVD risk <7.5% and in 20% this risk was < 5%! In the group with an ASCVD risk <5%, a large proportion was admitted for NSTEMI and UA complications. The authors remarked that if the USPSTF recommendations had been used (>10% 10-year ASCVD risk) an even larger number of the ACS patients would not have allocated to statin therapy. The outcomes of this analysis show that, despite the in 2013 released ACC/AHA guidelines, the proportion of patients using the appropriate statin type + dosage has only improved marginally.
Bavishi A, Howard T, Kim JP et al. Treatment Gap in Primary Prevention Patients Presenting With Acute Coronary Syndrome. Am J Cardiol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30497653
Relevant publications
  1. Zhang L, Zhang S, Yu Y et al. Efficacy and safety of rosuvastatin vs. atorvastatin in lowering LDL cholesterol : A meta-analysis of trials with East Asian populations. Herz 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30483816
  2. Capoulade R, Yeang C, Chan KL et al. Association of Mild to Moderate Aortic Valve Stenosis Progression With Higher Lipoprotein(a) and Oxidized Phospholipid Levels: Secondary Analysis of a Randomized Clinical Trial. JAMA cardiology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30476957
  3. Barkas F, Elisaf M, Rizos EC, Liberopoulos E. Bridging the treatment gap in patients at 'extreme' cardiovascular risk: Evidence from a lipid clinic. Atherosclerosis 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30471952
  4. Polster SP, Stadnik A, Akers AL et al. Atorvastatin Treatment of Cavernous Angiomas with Symptomatic Hemorrhage Exploratory Proof of Concept (AT CASH EPOC) Trial. Neurosurgery 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30476251
  5. Pertzov B, Eliakim-Raz N, Atamna H et al. Hydroxymethylglutaryl-CoA reductase inhibitors (statins) for the treatment of sepsis in adults - a systematic review and meta-analysis. Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30472427
  6. Heeney SA, Tjugum SL, Corkish ME, Hollis IB. Safety and tolerability of high intensity statin therapy in heart transplant patients receiving immunosuppression with tacrolimus. Clinical transplantation 2018:e13454. http://www.ncbi.nlm.nih.gov/pubmed/?term=30485535
  7. O'Donnell TFX, Boitano LT, Deery SE et al. Factors associated with postoperative renal dysfunction and the subsequent impact on survival after open juxtarenal abdominal aortic aneurysm repair. Journal of vascular surgery 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30477939
  8. Navaneethan SD, Akeroyd JM, Ramsey D et al. Facility-Level Variations in Kidney Disease Care among Veterans with Diabetes and CKD. Clin J Am Soc Nephrol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30498000
  9. Mudyanadzo TA. Endothelial Progenitor Cells and Cardiovascular Correlates. Cureus 2018; 10:e3342. http://www.ncbi.nlm.nih.gov/pubmed/?term=30473975
  10. Kim YH, Her AY, Jeong MH et al. Two-year outcomes of statin therapy in patients with acute myocardial infarction with or without dyslipidemia after percutaneous coronary intervention in the era of new-generation drug-eluting stents within Korean population: Data from the Korea Acute Myocardial Infarction Registry. Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30474346
  11. Baik SY, Kim H, Yang SJ et al. Long-term effects of various types of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on changes in glomerular filtration rate in Korea. Frontiers of medicine 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30483915
  12. Kim Y, Kim TW, Han SW et al. A Single Arm, Phase II Study of Simvastatin Plus XELOX and Bevacizumab as First-Line Chemotherapy in Metastatic Colorectal Cancer Patients. Cancer research and treatment : official journal of Korean Cancer Association 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30477287
  13. de Jager H, Suleman F. The impact of generics and generic reference pricing on candesartan and rosuvastatin utilisation, price and expenditure in South Africa. Int J Clin Pharm 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30478491
  14. Chan P, Shao L, Tomlinson B et al. An evaluation of pitavastatin for the treatment of hypercholesterolemia. Expert Opin Pharmacother 2018:1-11. http://www.ncbi.nlm.nih.gov/pubmed/?term=30482061
Miscellaneous publications
  1. Su J, Fang M, Tian B et al. Atorvastatin protects cardiac progenitor cells from hypoxia-induced cell growth inhibition via MEG3/miR-22/HMGB1 pathway. Acta biochimica et biophysica Sinica 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30481260
  2. Song ZC, Chen L, Zhang D et al. [Rosuvastatin protects acute myocardial infarction rats through autophagy regulation via AMPK signaling]. Zhonghua yi xue za zhi 2018; 98:3536-3541. http://www.ncbi.nlm.nih.gov/pubmed/?term=30481906
  3. Matsushita M, Kawaguchi M. Immunomodulatory Effects of Drugs for Effective Cancer Immunotherapy. Journal of oncology 2018; 2018:8653489. http://www.ncbi.nlm.nih.gov/pubmed/?term=30498512
  4. Hajihasani Biouki M, Mobedi H, Karkhaneh A, Daliri Joupari M. Development of a simvastatin loaded injectable porous scaffold in situ formed by phase inversion method for bone tissue regeneration. The International journal of artificial organs 2018:391398818806161. http://www.ncbi.nlm.nih.gov/pubmed/?term=30482084
  5. Geng J, Xu H, Yu X et al. Rosuvastatin protects against oxidized lowdensity lipoproteininduced endothelial cell injury of atherosclerosis in vitro. Mol Med Rep 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30483737
  6. Dong L, Xue L, Zhang C et al. HSP90 interacts with HMGCR and promotes the progression of hepatocellular carcinoma. Mol Med Rep 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30483734
  7. Bocate KP, Reis GF, de Souza PC et al. Antifungal activity of silver nanoparticles and simvastatin against toxigenic species of Aspergillus. International journal of food microbiology 2018; 291:79-86. http://www.ncbi.nlm.nih.gov/pubmed/?term=30476736
  8. Gulzar M, Ali S, Khan FI et al. Binding mechanism of caffeic acid and simvastatin to the integrin linked kinase for therapeutic implications: A comparative docking and MD simulation studies. Journal of biomolecular structure & dynamics 2018:1-37. http://www.ncbi.nlm.nih.gov/pubmed/?term=30488773
  9. Dai M, Chen Y, Mei X. Pravastatin sodium attenuated TREM-1-mediated inflammation in human peripheral blood mononuclear cells. Biochem Biophys Res Commun 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30473214
  10. Ahmed IS, El-Hosary R, Hassan M et al. Correction to "Efficacy and Safety Profiles of Oral Atorvastatin-Loaded Nanoparticles: Effect of Size Modulation on Biodistribution". Molecular pharmaceutics 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30484318
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