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Update - Week 42,  2017 
 
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

CVD risk guidelines and tools – what can we learn from existing initiatives?
Although CVD risk management guidelines share more similarities than differences, the discussions surrounding the superiority of one over the other seems to be a source of never ending polemics. In this review, the authors provide a relevant acumen on the implementation of guideline based management strategies. Their objective was to analyze and compare how GP’s from Australia and New Zealand interpret and apply their CVD risk management guidelines in to actionable statin initiation. Two observational studies, on primary care supervized CVD risk management. The PREDICT-CVD (New Zealand) and AusHeart (Australia). The PREDICT-CVD (N=126 519) is used by 1/3 of all New Zealand GP’s. It is a web based CVD risk assessment and management registry that was started January 1st, 2007 and data collected until June 30th 2017 was used for this analysis. The AusHeart is a survey on CVD risk management. Overall 534 GP’s provided data on 1 281 patients; from April 1st, 2008 - June 30th, 2008. Age of evaluated patients was 55 – 75 years and they were free of CVD at inclusion. The NZ physicians based their decision to start with statin on absolute CVD risk, in contrast with their Australian counterparts for whom a number of other factors, e.g. total cholesterol, LDL-C and diabetes, weighed in on their decision to initiate a statin. The authors emphasize in their conclusions that (national) organizations aiming to improve CVD management should base their recommendations on an absolute risk calculation as well as provide distinct directives that incorporate drug reimbursement rules. They prefer electronic registries with integrated decision-making tools as well as outcome appraisal to improve future clinical care for high CVD risk patients.   
Schilling C, Knight J, Mortimer D et al. Australian general practitioners initiate statin therapy primarily on the basis of lipid levels; New Zealand general practitioners use absolute risk. Health Policy 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29042060
 
How to estimate baseline LDL-C in statin (+ezetimibe) treated FH patients
Accurately diagnosing FH patients depends to a large extend on baseline LDL-C levels. When patients are already using statins, base-line levels before treatment are not always available or reliable reproduced by patients. The health care professional will then have to estimate this values  based on personal experience and/or recent articles, that supplies data on LDL-C lowering efficacy of different lipid lowering drugs. In this analysis, the authors set out to evaluate their model for imputation of baseline LDL-C levels containing the complete spectrum of available statins as well as Ezetimibe. They retrospectively analyzed LDL-C data of 951 Canadian FH patients within a 18 months after staring and compared the observed reductions with the imputed observed LDL-C decreases. Overall the mean LDL-C at baseline was 243 (± 2.0) mg/dl and the imputed LDL-C 244.2 (± 2.6) mg/dl.; P=0.48). No differences were observed based on gender or in percent reduction between observed and expected for individual doses or types of statin or ezetimibe. The data shared in this publication can support physicians that manage FH patients in their diagnostic evaluations as well as treatment decisions.
Ruel I, Aljenedil S, Sadri I et al. Imputation of Baseline LDL Cholesterol Concentration in Patients with Familial Hypercholesterolemia on Statins or Ezetimibe. Clinical chemistry 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29038147

Are organ transplant patients better protected with statins? 
The purpose of this systematic review and meta-analysis was to provide an update on the effects of statins after a renal transplant, adding the published data of recent trials. For the final analysis 7 articles were included providing the data on 1870 transplanted patients the received a statin and 3 339 patients who did not. The authors were unable to show a reduction of organ rejection/graft survival in the overall analysis, but after adjustment for age, sex and serum creatinine statins did provide a benefit on graft survival, HR: 0.80 (0.69-0.92; P = .003). Overall survival improved in the statin-users, HR`; 0.75 (0.63-0.88; P = .003), after adjustment of confounding variables. Most data were collected in studies where fluvastatin was used and the authors question of these effects can be reliable extrapolated to other more potent statins used with higher dosages. Despite the limitations of this meta-analysis and the limitations of the small number of studies that predominantly used fluvastatin, the authors point out that the benefits of statins in renal transplant patients are convincing and doctors managing renal transplant patients should make statin prescription a practice routine. 
Rostami Z, Moteshaker Arani M, Salesi M et al. Effect of Statins on Patients and Graft Survival in Kidney Transplant Recipients: a Survival Meta-analysis. Iran J Kidney Dis 2017; 11:329-338. http://www.ncbi.nlm.nih.gov/pubmed/?term=29038386
 
HELP syndrome and statins; a case reports with surprising outcomes
The role of statins in non-lipid related diseases has not been explored as thoroughly as for CVD. However more case reports, retrospective analyses of completed studies and small clinical trials focusing on surrogate markers are increasing in numbers. In this very provocative case report the impact of statin was remarkable! A female patient that had 3 complicated pregnancies due to HELLP (hemolysis, elevated liver enzymes and low platelets) syndrome. This resulted in 3 miscarriages and severe complications during the pregnancies for the pregnant patient as well. Based on reports on patients that responded very well to pravastatin to prevent pre-eclampsia complicated pregnancies and miscarriages this patient started with pravastatin 10 mg at week 12. In addition, the customary therapeutic regimen was initiated as well. She had an elective cesarean section at week 37, and healthy 2920 gram weighing boy was born. Both, patient and
newborn, made an uncomplicated postoperative/postnatal course and were discharged on day 3. The patient was under close surveillance for the whole pregnancy. Gestational diabetes developed in the 3rd trimester but no other complications manifested for the mother and the unborn child. The authors suggested proper designed trials were needed to confirm the notable results they observed.
Otten LA, van der Ven K, Kuhr M et al. Pravastatin for prevention of HELLP syndrome: A case report. Medicine (Baltimore) 2017; 96:e8229. http://www.ncbi.nlm.nih.gov/pubmed/?term=29049209
 
Should statins be part of the treatment portfolio in cancer patients at risk for VTE?
The protective role of statins in VTE prevention remains enigmatic. In this short communication, the authors share the data of the French EDITH case control study. This cancer related VTE registry, collected data between May 2000 and November 2011. Retrospectively 182 Cancer related thrombosis cases were matched with 182 controls. BMI, more frequent metastasis and VTE family history were associated with an increased VTE risk. Clopidogrel and aspirin use were correlated with a lower VTE risk. Aspirin use was less frequently seen in the controls vs cases, 2.8% vs. 18.1%, similar the percentage of patient that developed VTE and using statins was low as well, 3.3% versus 15.4% in the controls. The use of anti-platelets drugs showed a significant lower VTE incidence, 89% and 82% risk reduction in respectively aspirin and Clopidogrel users. In univariate analysis statin use showed a marked 81% reduction of VTE’s; OR: 0.11 (0.07-0.46). In the adjusted analysis, the risk was reduced by 67%; OR: 0.33 (0.12-0.90). This is in line with previous studies of an Austrian and US prospective cohort, where risk reductions of 57% and 67% were observed. The authors acknowledge that their study is a retrospective analysis of a relatively small number of patients and that a randomized clinical trial is urgently needed to confirm these findings.
De Moreuil C, Le Mao R, Tromeur C et al. Association between statin exposure and venous thromboembolism risk in cancer patients. Data from the EDITH case-control study. Eur J Intern Med 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29046258
 
Can circulating PCSK9/LDLR levels predict outcomes in heart failure patients?
The Biology Study to Tailored Treatment in Chronic Heart Failure (BIOSTAT-CHF) is a large multi-center (n=69) and multi-national, European (N=11) HF registry. In this registry data was collected on patients (N=2 516) with worsening HF, from 2010 -2012. At the start of the study PCSK9 and LDL-R levels were measured. Over the two years follow up 896 (41.2%) of the patients experienced one of the composite endpoints of the study and 569 (26.2%) deaths were observed. A multivariate analysis showed a positive correlation between PCSK9 levels and mortality; HR 1.24 (1.04-1.49; P=0.020) this was also the case for the composite endpoint (mortality or unscheduled hospitalizations for HF), HR: 1.21 (1.05-1.40; p=0.010). This contrasted with the LDL-R levels, where a protective effect was observed, mortality; HR 0.86 (0.76-0.98; P=0.025) and for the composite endpoint, HR: 0.92 (0.83-1.01; p=0.087). Adding the PCSK9 and LDL-R plasma concentrations improved the BIOSTAT-CHF risk score. Whether PCSK9-ab have an effect, beyond plasma LDL-C reduction, needs to be addressed in future randomized clinical trials.  
Bayes-Genis A, Nunez J, Zannad F et al. The PCSK9-LDL Receptor Axis and Outcomes in Heart Failure: BIOSTAT-CHF Subanalysis. J Am Coll Cardiol 2017; 70:2128-2136. http://www.ncbi.nlm.nih.gov/pubmed/?term=29050560
Relevant publications
  1. Sim DS, Jeong MH. Differences in the Korea Acute Myocardial Infarction Registry Compared with Western Registries. Korean Circ J 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29035427
  2. Hickson RP, Robinson JG, Annis IE et al. Changes in Statin Adherence Following an Acute Myocardial Infarction Among Older Adults: Patient Predictors and the Association With Follow-Up With Primary Care Providers and/or Cardiologists. J Am Heart Assoc 2017; 6. http://www.ncbi.nlm.nih.gov/pubmed/?term=29051213
  3. Kiyosue A. Nonfasting TG/HDL-C ratio seems a good predictor of MACE in CAD patients with statin therapy. Could it be a treatment target? J Cardiol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29033056
  4. Garshick M, Underberg JA. The Use of Primary Prevention Statin Therapy in Those Predisposed to Atherosclerosis. Curr Atheroscler Rep 2017; 19:48. http://www.ncbi.nlm.nih.gov/pubmed/?term=29038899
  5. Franklin JM, Donneyong MM, Desai RJ et al. Variation in adherence to medications across the healthcare system in two comparative effectiveness research cohorts. Journal of comparative effectiveness research 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29039693
  6. Arrieta A, Hong JC, Khera R et al. Updated Cost-effectiveness Assessments of PCSK9 Inhibitors From the Perspectives of the Health System and Private Payers: Insights Derived From the FOURIER Trial. JAMA cardiology 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29049467
  7. Lu C, Jia H, Wang Z. High-dose atorvastatin reduces the risk of cardiovascular events in patients with percutaneous coronary intervention. Oncotarget 2017; 8:70356-70365. http://www.ncbi.nlm.nih.gov/pubmed/?term=29050285
  8. An J, Shi F, Liu S et al. Preoperative statins as modifiers of cardiac and inflammatory outcomes following coronary artery bypass graft surgery: a meta-analysis. Interact Cardiovasc Thorac Surg 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29049804
  9. Allard NAE, Schirris TJJ, Verheggen RJ et al. Statins affect skeletal muscle performance: evidence for disturbances in energy metabolism. J Clin Endocrinol Metab 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29040646
  10. Al-Salameh A, Bucher S, Bauduceau B et al. Gender-Related Differences in the Control of Cardiovascular Risk Factors in Primary Care for Elderly Patients with Type 2 Diabetes: A Cohort Study. Canadian journal of diabetes 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29037572
  11. Zullo AR, Sharmin S, Lee Y et al. Secondary Prevention Medication Use After Myocardial Infarction in U.S. Nursing Home Residents. J Am Geriatr Soc 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29044457
  12. Rong X, Yin J, Wang H et al. Statin treatment may lower the risk of postradiation epilepsy in patients with nasopharyngeal carcinoma. Epilepsia 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29034463
  13. Rajput TA, Naveed AK, Farooqi ZR, Khan S. Effects of two functionally important SLCO1B1 gene polymorphisms on pharmacokinetics of atorvastatin. Pak J Pharm Sci 2017; 30:1363-1370. http://www.ncbi.nlm.nih.gov/pubmed/?term=29039339
  14. Ofori S, Dodiyi-Manuel S, Akpa MR. Comparison of 3 risk estimators to guide initiation of statin therapy for primary prevention of cardiovascular disease. J Clin Lipidol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29050979
  15. Murasato Y, Kinoshita Y, Yamawaki M et al. Effect of low-density lipoprotein cholesterol on the geometry of coronary bifurcation lesions and clinical outcomes of coronary interventions in the J-REVERSE registry. Cardiovascular intervention and therapeutics 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29052106
  16. Leiter A, Bickell NA, LeRoith D et al. Statin Use and Breast Cancer Prognosis in Black and White Women. Hormones & cancer 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29052171
  17. Eymard F, Parsons C, Edwards MH et al. Statin use and knee osteoarthritis progression: Results from a post-hoc analysis of the SEKOIA trial. Joint Bone Spine 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29037516
  18. El Khoury P, Elbitar S, Ghaleb Y et al. PCSK9 Mutations in Familial Hypercholesterolemia: from a Groundbreaking Discovery to Anti-PCSK9 Therapies. Curr Atheroscler Rep 2017; 19:49. http://www.ncbi.nlm.nih.gov/pubmed/?term=29038906
Miscellaneous publications
  1. Wang Y, Chen Q, Tan Q et al. Simvastatin accelerates hematoma resolution after intracerebral hemorrhage in a PPARgamma-dependent manner. Neuropharmacology 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29054366
  2. Varshosaz J, Taymouri S, Minaiyan M et al. Development and In vitro/in vivo evaluation of HPMC/chitosan gel containing simvastatin loaded self-assembled nanomicelles as a potent wound healing agent. Drug development and industrial pharmacy 2017:1-31. http://www.ncbi.nlm.nih.gov/pubmed/?term=29043860
  3. Uchida M, Tajima Y, Kakuni M et al. Organic anion transporting polypeptides (OATPs)-mediated drug-drug interaction study between rosuvastatin and cyclosporine A in chimeric mice with humanized liver. Drug metabolism and disposition: the biological fate of chemicals 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29051147
  4. Thongnak L, Pongchaidecha A, Jaikumkao K et al. The additive effects of atorvastatin and insulin on renal function and renal organic anion transporter 3 function in diabetic rats. Scientific reports 2017; 7:13532. http://www.ncbi.nlm.nih.gov/pubmed/?term=29051569
  5. Tate R, Zona E, De Cicco R et al. Simvastatin inhibits the expression of stemnessrelated genes and the metastatic invasion of human cancer cells via destruction of the cytoskeleton. International journal of oncology 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29039527
  6. Li Y, Jiang T, Fu X et al. [Retracted] Atorvastatin protects cardiomyocytes against OGD/Rinduced apoptosis by inhibiting miR199a5p. Mol Med Rep 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29039522
  7. Carroll CB, Wyse RKH. Simvastatin as a Potential Disease-Modifying Therapy for Patients with Parkinson's Disease: Rationale for Clinical Trial, and Current Progress. Journal of Parkinson's disease 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29036837
  8. Hirpara MR, Manikkath J, Sivakumar K et al. Long circulating PEGylated-chitosan nanoparticles of rosuvastatin calcium: Development and in vitro and in vivo evaluations. International journal of biological macromolecules 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29042279
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This activity is supported by an educational grant from Pfizer.