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Update - Week 19, 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

Japanese stable CAD patients benefit from “Lower is Better” strategy
The “Lower is Better” strategy iss based on evidence accumulated in numerous statin trials. The aim of the REAL-CAD study was to establish if this strategy is applicable to Asian patients as well. The need of a high dose statins and tolerability remains an ardently debated issue for Asians and Japanese in particular. In the REAL-CAD study  13 054 Japanese stable CAD patients were included that, after a run-in phase Using pitavastatin 1 mg, achieved and LDL-c < 120 mg/dl. Patients were than randomized to pitavastatin 1 mg (N=6526) or pitavastatin 4 mg (N=6528). The primary endpoint was a composite of CV death, non-fatal MI, non fata IS, or unstable angina requiring emergency re-vascularization. For the secondary endpoint non-target lesion revascularizations were added to the primary endpoint. Baseline LDL-c where comparable; 87.7 and 88.1 in both groups. Patients using 4 mg pitavastatin lowered their LD-c by an additional 14.7 mg/dl (16.9%) compared to patients that continued with 1 mg (p<0.001).  After a median follow-up of 3.9 years reported primary endpoints were significantly less in the patients treated with the higher dosage of pitavastatin; 226 patients (4.3%) vs 334 patients (5.4%); HR 0.81 (0.69-0.95; p=0.001). Similar benefits were observed for the secondary endpoints: 489 patients (7.9%) vs 600 patients (9.7%); HR 0.83 (0.73—0.93; p=0.002). All-cause mortality MI and re-vasc’s were significantly reduced as well. The authors concluded that in Japanese stable CAD patients a “Lower is Better” strategy significantly reduced cardiovascular events.
Taguchi I, Iimuro S, Iwata H et al. High-Dose Versus Low-Dose Pitavastatin in Japanese Patients With Stable Coronary Artery Disease (REAL-CAD): A Randomized Superiority Trial. Circulation 2018; 137:1997-2009. http://www.ncbi.nlm.nih.gov/pubmed/?term=29735587
Barter PJ. High- Versus Low-Dose Statin: Effects on Cardiovascular Events and All-Cause Death. Circulation 2018; 137:2013-2015. http://www.ncbi.nlm.nih.gov/pubmed/?term=29735589
Teramoto T. Extending the "Lower is Better" Principle to Japanese and Possibly Other Asian Populations. Circulation 2018; 137:2010-2012. http://www.ncbi.nlm.nih.gov/pubmed/?term=29735588
 
Difference in statin use in elderly vs younger patients?
Statin use in elderly patients has been tested in a relative small number of RCT studies. The authors of this study aimed to evaluate statins safety and tolerability of statins in an elderly cohort of statin eligible patients. The PALM registry consists of 7 736 ASCVD, or at high risk for ASCVD, patients from 138 cardiology, primary care and endocrinology practices in the US. Data was collected in a cross-sectional manner at enrolment in 2015. Patients >75 years were compared to patients ≤ 75 years (N= 1704; 25%). Treatments strategies for primary prevention were comparable in both groups, any statin 62,6% vs 63.1% (P=0.83) and high dose statin 10.2% vs 12.3% (p=0.14) for >75 years vs ≤ 75 years respectively. In a Secondary prevention setting elderly patients were less likely to be treated with statins and even less used high-intensity statins; 80.1% versus 84.2% (P=0.003); OR 0.81 (0.66–1.01; P=0.06) and 23.5% versus 36.2% (P<0.0001) OR 0.54; (0.45–0.65; P=0.0001) respectively. Tolerability issues including myalgia’s were reported significantly less in elderly patients; 41.3% versus 46.6%; P=0.003. Myalgias 27.3% versus 33.3%; P<0.001. The authors concluded that statin use was comparable in elderly vs younger patients in a primary prevention setting, but in secondary prevention elderly were less likely to be treated with (high intensity) statins. Statin intolerability was not observed more frequently in elderly patients.
Nanna MG, Navar AM, Wang TY et al. Statin Use and Adverse Effects Among Adults >75 Years of Age: Insights From the Patient and Provider Assessment of Lipid Management (PALM) Registry. J Am Heart Assoc 2018; 7. http://www.ncbi.nlm.nih.gov/pubmed/?term=29739801
 
Shared decision making and statin use – a patients perspective
Doctor – patient communication is often neglected because of time restrains. In this study the authors evaluated the patient’s perception on statin use comparing statin users with patients that stopped taking statins.  An on-line survey was used to evaluate US patients (N=5 014) on disease perspective, medication use, side effects and recall of communication with their health care provider. Of the participants 94% were current statin users and 6% had stopped taking statins. Past users were more often females (64% vs 47%), younger <65 years (57% vs 49%), and had fewer CVD related risk factors (hypertension 58% vs 69%, DM2 17% vs 27% and CHD 4% vs 9%; all P< 0.05). Statin switching was reported in 43% of current users vs 47% of past users. Current users were more likely than past users to switch due to “it was recommended” (27% vs 8%), medication costs (14 vs 7%), lack of insurance coverage (10% vs 2%), desire for a generic statin (14 vs 2%), lack of cholesterol efficacy (13% vs 6%), or lack of triglyceride efficacy (11% vs 5%) (all p<0.05). Past users were more likely than current users to switch because of muscle and/or joint pain (42% vs 17%), other symptoms (29% vs 9%), and risk of medication interference (9% vs 3%) (all p<0.05). Patients reported the need for instructions or explanations of why a statin is selected as well as side effects and potential drug-drug interactions. They often did not recall these instructions. Current statin users that switched statins cited cost and coverage of statins as well as lipid lowering efficacy as the most important reasons for switching statins. For past users, side effects and risk of drug-drug interactions were their main reason for stopping statins. The results from this survey highlight the need to improve shared decision communications between patients and health care providers.
Brinton EA. Understanding Patient Adherence and Concerns with STatins and MedicatION Discussions with Physicians (ACTION): A Survey on the Patient Perspective of Dialogue with Healthcare Providers Regarding Statin Therapy. Clin Cardiol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29749101
 
Should re-initiating statins become a SOP after ACS hospital discharge?
There is a considerable chance that patients starting statins will stop using them. Re-initiating statins was shown to be effective and a majority of those who stopped will be able to successfully re-start their medications. The role of healthcare professionals is pivotal for this to occur. In this retrospective analysis (2007-2012) of a large US Medicare database, CVD patients discharged from hospital with a statin prescription were followed for 6 months (N=158 795). Treatment discontinuations (≥ 60 consecutive days without statins) were observed in 24 416 patients. Re-initiation within 12 months of the discontinuation date was noted in 13 136 patients. Healthcare interactions that had a significant impact on statin re-initiation were: lipid panel testing OR 2.65 (1.93–3.65), outpatient primary care OR 1.31 (1.23–1.40), outpatient cardiologist care OR 1.38 (1.28–1.50), emergency department visits OR 1.77 (1.31–2.40), CHD hospitalizations OR 3.16 (2.41–4.14) and non–CHD hospitalizations OR 1.73 (1.49–2.01).The Authors concluded that in a routine care setting , there are missed opportunities for restarting statins in patients at very high CVD risk (secondary prevention). Noted is the large percentage (> 15%) of patients that fail to continue using statins <6 months after hospital discharge!
Booth JN, 3rd, Colantonio LD, Rosenson RS et al. Healthcare Utilization and Statin Re-Initiation Among Medicare Beneficiaries With a History of Myocardial Infarction. J Am Heart Assoc 2018; 7. http://www.ncbi.nlm.nih.gov/pubmed/?term=29739799
 
Pitavastatin vs Atorvastatin in Asian patients are they comparable?
In this meta-analysis pitavastatin and atorvastatin where compared in trials with Asian participants. Although dosages of 1-2 mg vs 10-20 mg would be described as low – moderate intensity in the US and Europe the authors defined this as high intensity, based on common practice and guidelines from Asian countries e.g. Japan and Korean. They not only queried differences in LDL-c and HDL-c but aimed to compare effects on glycemic control and regression of atherosclerosis, based on IVUS studies, as well. Numerous literature source were queried and  for the final analysis 11 trials with a total of 1733 participants were included. Only trials where both statins were compared directly and that reported LDL-c, HDL-c, HbA1c and IVUS changes, were included. For pitavastatin vs atorvastatin the mean disparities for LDL-c and HDL-c were 2.51 (1.17–3.86; I2=48%; P=0.0003] and 2.17 (1.42–2.91; I2=40%; P<0.00001), respectively, for pitavastatin. No significant differences were observed for HbA1C −0.15 (−1.44–1.15; I2=0%; P=0.83) for pitavastatin compared with atorvastatin. The IVUS parameters plaque volume, lumen volume, and external elastic membrane changes were similar as well; −0.93 (−3.04–1.19; I2=50%; P=0.39), 0.17 (−2.91–3.26; I2=0%; P=0.91), and −0.43 (−1.96–1.11; I2=4%; P=0.58), respectively. In this meta-analysis Atorvastatin was proven to have superior benefits of LDL-c reductions as well HDL-c increases. Despite earlier claims of pitavastatin for improving glycemic control no differences could be discerned when compared to Atorvastatin. Limitations of this meta-analysis; the small number studies, limited number of participants, heterogeneity of patients, relatively low dosages of the statins and Asian ethnicity of all participants, dictate that these preliminary finding need to be confirmed in proper designed large randomized trials.
Liu H, Zhang M, Li D et al. Effect of pitavastatin and atorvastatin on regression of atherosclerosis assessed using intravascular ultrasound: a meta-analysis. Coronary artery disease 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29738341
 
 
Relevant publications
  1. Weng S, Kai J, Tranter J et al. Improving identification and management of familial hypercholesterolaemia in primary care: Pre- and post-intervention study. Atherosclerosis 2018; 274:54-60. http://www.ncbi.nlm.nih.gov/pubmed/?term=29751285
  2. Weisshaar S, Zeitlinger M. Vaccines Targeting PCSK9: A Promising Alternative to Passive Immunization with Monoclonal Antibodies in the Management of Hyperlipidaemia? Drugs 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29737499
  3. Ross S, Gerstein H, Pare G. The Genetic Link Between Diabetes and Atherosclerosis. Can J Cardiol 2018; 34:565-574. http://www.ncbi.nlm.nih.gov/pubmed/?term=29731020
  4. Nakamura Y, Asaumi Y, Miyagi T et al. Comparison of Long-Term Mortality in Patients With Previous Coronary Artery Bypass Grafting Who Underwent Percutaneous Coronary Intervention With Versus Without Optimal Medical Therapy. Am J Cardiol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29747859
  5. Ridruejo E, Romero-Caimi G, Obregon MJ et al. Potential Molecular Targets of Statins in the Prevention of Hepatocarcinogenesis. Annals of hepatology 2018; 17:490-500. http://www.ncbi.nlm.nih.gov/pubmed/?term=29735800
  6. Nakamura Y, Asaumi Y, Miyagi T et al. Comparison of Long-Term Mortality in Patients With Previous Coronary Artery Bypass Grafting Who Underwent Percutaneous Coronary Intervention With Versus Without Optimal Medical Therapy. Am J Cardiol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29747859
  7. Ma B, Sun J, Diao S et al. Effects of perioperative statins on patient outcomes after noncardiac surgery: a meta-analysis. Annals of medicine 2018:1-8. http://www.ncbi.nlm.nih.gov/pubmed/?term=29741972
  8. Humphries SE, Cooper JA, Seed M et al. Coronary heart disease mortality in treated familial hypercholesterolaemia: Update of the UK Simon Broome FH register. Atherosclerosis 2018; 274:41-46. http://www.ncbi.nlm.nih.gov/pubmed/?term=29751283
  9. Gonzalez-Juanatey JR. Update to the Consensus Document on Clinical Use of the Polypill: New Dose Containing Atorvastatin 40 mg. Rev Esp Cardiol (Engl Ed) 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29752030
  10. Elbadawi-Sidhu M, Baillie RA, Zhu H et al. Pharmacometabolomic signature links simvastatin therapy and insulin resistance. Metabolomics : open access 2017; 13. http://www.ncbi.nlm.nih.gov/pubmed/?term=29732238
  11. Cui JY, Zhou RR, Han S et al. Statin therapy on glycemic control in type 2 diabetic patients: A network meta-analysis. Journal of clinical pharmacy and therapeutics 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29733433
  12. Chen X, Wang S, Lin L et al. Drug effect of atorvastatin on middle cerebral atherosclerotic stenosis and high resolution NMR diagnosis. Pak J Pharm Sci 2018; 31:1169-1173. http://www.ncbi.nlm.nih.gov/pubmed/?term=29737302
  13. Cano-Corres R, Candas-Estebanez B, Padro-Miquel A et al. Influence of 6 genetic variants on the efficacy of statins in patients with dyslipidemia. Journal of clinical laboratory analysis 2018:e22566. http://www.ncbi.nlm.nih.gov/pubmed/?term=29732606
  14. Booth JN, 3rd, Colantonio LD, Rosenson RS et al. Healthcare Utilization and Statin Re-Initiation Among Medicare Beneficiaries With a History of Myocardial Infarction. J Am Heart Assoc 2018; 7. http://www.ncbi.nlm.nih.gov/pubmed/?term=29739799
  15. Virani SS, Kennedy KF, Akeroyd JM et al. Variation in Lipid-Lowering Therapy Use in Patients With Low-Density Lipoprotein Cholesterol >/=190 mg/dL: Insights From the National Cardiovascular Data Registry-Practice Innovation and Clinical Excellence Registry. Circ Cardiovasc Qual Outcomes 2018; 11:e004652. http://www.ncbi.nlm.nih.gov/pubmed/?term=29748356
  16. Ray KK, Stoekenbroek RM, Kallend D et al. Effect of an siRNA Therapeutic Targeting PCSK9 on Atherogenic Lipoproteins: Pre-Specified Secondary End Points in ORION 1. Circulation 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29735484
  17. Piechota-Polanczyk A, Kopacz A, Kloska D et al. Simvastatin Treatment Upregulates HO-1 in Patients with Abdominal Aortic Aneurysm but Independently of Nrf2. Oxidative medicine and cellular longevity 2018; 2018:2028936. http://www.ncbi.nlm.nih.gov/pubmed/?term=29743974
  18. Paraskevas KI. Letter to the Editor: Effect of Statin Therapy on Survival After Abdominal Aortic Aneurysm Repair: A Systematic Review and Meta-analysis. World journal of surgery 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29750322
  19. Luzum JA, Luzum MJ. Physicians' attitudes toward pharmacogenetic testing before and after pharmacogenetic education. Personalized medicine 2016; 13:119-127. http://www.ncbi.nlm.nih.gov/pubmed/?term=29749904
  20. Kumar R, Tonkin A, Liew D, Zomer E. The cost-effectiveness of PCSK9 inhibitors - The Australian healthcare perspective. Int J Cardiol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29731350
  21. Kirhmajer MV, Sarinic VM, Simicevic L et al. Rosuvastatin-induced rhabdomyolysis - Possible role of ticagrelor and patients' Pharmacogenetic profile. Basic & clinical pharmacology & toxicology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29734517
  22. Kim YS, Park MS, Lee JH et al. Effect of Statins on Survival Following Stroke in Patients With Cancer. Frontiers in neurology 2018; 9:205. http://www.ncbi.nlm.nih.gov/pubmed/?term=29740381
  23. Kim S, Kim H, Kim E et al. Utilization Patterns of Lipid-lowering Therapies in Patients With Atherosclerotic Cardiovascular Disease or Diabetes: A Population-Based Study in South Korea. Clinical therapeutics 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29735297
  24. Hesami O, Sistanizad M, Asadollahzade E et al. Comparing the Effects of Atorvastatin With Sodium Valproate (Divalproex) on Frequency and Intensity of Frequent Migraine Headaches: A Double-blind Randomized Controlled Study. Clinical neuropharmacology 2018; 41:94-97. http://www.ncbi.nlm.nih.gov/pubmed/?term=29746282
  25. Gordon JA, Buonerba C, Pond G et al. Statin use and survival in patients with metastatic castration-resistant prostate cancer treated with abiraterone or enzalutamide after docetaxel failure: the international retrospective observational STABEN study. Oncotarget 2018; 9:19861-19873. http://www.ncbi.nlm.nih.gov/pubmed/?term=29731989
  26. Fujisue K, Shirakawa T, Nakamura S et al. Dose-dependent INhibitory effect of rosuVastatin In Japanese patienTs with Acute myocardial infarcTION on serum concentration of matrix metalloproteinases - INVITATION trial. J Cardiol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29735336
  27. Balaguer C, Peralta A, Rios A et al. Effects of simvastatin in chronic obstructive pulmonary disease: Results of a pilot, randomized, placebo-controlled clinical trial. Contemporary clinical trials communications 2016; 2:91-96. http://www.ncbi.nlm.nih.gov/pubmed/?term=29736450
Miscellaneous publications
 
 
  1. Yang Y, Wang J, He H et al. Influence of Fatty Acid Modification on Uptake of Lovastatin-Loaded Reconstituted High Density Lipoprotein by Foam Cells. Pharm Res 2018; 35:134. http://www.ncbi.nlm.nih.gov/pubmed/?term=29736804
  2. Syam Das S, Nair SS, Indira M. Atorvastatin modulates drug transporters and ameliorates nicotine-induced testicular toxicity. Andrologia 2018:e13029. http://www.ncbi.nlm.nih.gov/pubmed/?term=29740849
  3. Li X, Wu F, Zhang Y et al. Discontinuation of simvastatin leads to a rebound phenomenon and results in immediate peri-implant bone loss. Clinical and experimental dental research 2016; 2:65-72. http://www.ncbi.nlm.nih.gov/pubmed/?term=29744151
  4. Kong B, Wang X, Yang W et al. Effects of simvastatin on the function of splenic CD4(+) and CD8(+) T cells in sepsis mice. Immunologic research 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29752615
  5. Ito Y, Maejima Y, Tamura N et al. Synergistic effects of HMG-CoA reductase inhibitor and angiotensin II receptor blocker on load-induced heart failure. FEBS open bio 2018; 8:799-816. http://www.ncbi.nlm.nih.gov/pubmed/?term=29744294
  6. Hamidreza Kheiri M, Alimohammadi N, Danafar H. Preparation of biocompatible copolymeric micelles as a carrier of atorvastatin and rosuvastatin for potential anticancer activity study. Pharmaceutical development and technology 2018:1-11. http://www.ncbi.nlm.nih.gov/pubmed/?term=29741465
  7. Carson RA, Rudine AC, Tally SJ et al. Statins impact primary embryonic mouse neural stem cell survival, cell death, and fate through distinct mechanisms. PLoS One 2018; 13:e0196387. http://www.ncbi.nlm.nih.gov/pubmed/?term=29738536
  8. Basyoni MMA, Fouad SA, Amer MF et al. Atorvastatin: In-Vivo Synergy with Metronidazole as Anti-Blastocystis Therapy. The Korean journal of parasitology 2018; 56:105-112. http://www.ncbi.nlm.nih.gov/pubmed/?term=29742864
  9. Zhou ZY, Huang B, Li S et al. Sodium tanshinone IIA sulfonate promotes endothelial integrity via regulating VE-cadherin dynamics and RhoA/ROCK-mediated cellular contractility and prevents atorvastatin-induced intracerebral hemorrhage in zebrafish. Toxicology and applied pharmacology 2018; 350:32-42. http://www.ncbi.nlm.nih.gov/pubmed/?term=29730311
  10. Iizuka-Ohashi M, Watanabe M, Sukeno M et al. Blockage of the mevalonate pathway overcomes the apoptotic resistance to MEK inhibitors with suppressing the activation of Akt in cancer cells. Oncotarget 2018; 9:19597-19612. http://www.ncbi.nlm.nih.gov/pubmed/?term=29731968
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