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Update - Week 28 - 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

Coronary microvascular dysfunction - undervalued and undertreated
The “Prinzmetal” or variant angina pectoris is characterized by anginal complaints not triggered by exertion or exercise but occurring at rest or even asleep. The underlying pathology is not obstructive CAD but coronary microvascular dysfunction (CMD). Patients are generally younger but the majority do have CVD risk factors and CMD is more frequently observed in women. In this review the authors share recent findings and emphasize the underestimated risk associated with this anginal variant. In the Women’s Ischemia Syndrome Evaluation Study (WISE), an increase in MACE, and surprisingly, heart failure hospitalization with preserved ejection in combination with resting diastolic dysfunction, was noted. CMD could be viewed as a precursor of pre-heart failure with preserved ejection fraction. Diagnostic strategies for CMD include invasive and not invasive procedures to evaluate coronary flow in response to vasodilator agent. Therapeutic approaches include high dose – high intensity statins, maximum tolerated ACE-I or ARB, β-blockers and aspirin combined with optimal lifestyle. What needs to be addressed are clinical outcome trials to evaluate the therapeutic strategies as well  as CVD outcomes and quality of life, to promote the suggested intervention into evidence based guidelines.
Wei J, Shufelt C, Bairey Merz CN. Women's health: making cardiovascular disease real. Current opinion in cardiology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29985202
Statin pretreatment shows added benefits post ischemic stroke
Can statin pretreatment (SP) have an impact beyond the reducing risk for major CV events. In this evaluated meta-analysis the authors looked at (observational) studies that looked at micro embolic signals (MES) , using trans cranial Doppler, in patients that suffered acute ischemic stroke related to cerebral artery stenosis  (>50%). Patients with statin pretreatment were compared to patients without. In a subgroup analysis, patients using atorvastatin 80 mg or rosuvastatin 40 mg were evaluated separately. In total 7 trials that included 610 patients were used for the final analysis. Statin pretreatment provided better protection from MES, RR = 0.67 (0.45-0.98). Studies that specifically reported MES burden (N=4) SP was related to reduced MES events: -0.92 (-1.64 — -0.19). IN the subgroup that used high dose – high intensity statins the benefits were more pronounced RR = 0.23 (0.06-0.88). Statin pretreatment protected ischemic stroke patients from MES presence and burden. The observational nature of this meta-analysis warrants confirmation in properly designed RCT’s. 
Safouris A, Katsanos AH, Kerasnoudis A et al. Statin Pretreatment and Microembolic Signals in Large Artery Atherosclerosis: A Systematic Review and Meta-Analysis. Stroke 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29991656
Increased risk in fetuses exposed to statin during first trimester
The increased global efforts to diagnose and treat FH patients as well as cardiovascular risk factors manifesting at a younger age, results in younger patients being treated with statins. In young women of child bearing age, unexpected pregnancies can happen and result in rising numbers of statin exposure during pregnancy. Limited data is available on the teratogenic effects of statins; to study the potential harms of statins during pregnancy the authors analyzed a cohort of 379 238 pregnancies of the Kayser Permanente Southern California registry (2013-2015). In this retrospective analysis 280 women exposed to statins during the first trimester were compared to 5282 pregnant women not exposed to statins. By using logistic regression and propensity score modeling, the risks of fetal harm after statin exposure in the first trimester were calculated. The risk for ventricular septal defects was significantly increased in statin exposed fetuses; OR 3.3 (1.8-6.0; P< 0.001). In the propensity score matched model; OR 4.7 (2.0-10.8; P<0.001). The authors concluded that despite the potential benefit of statins in the preventing of pre-eclampsia complications, and reducing long term CVD risk, statins should not be used by pregnant women.
Lee MS, Hekimian A, Doctorian T, Duan L. Statin exposure during first trimester of pregnancy is associated with fetal ventricular septal defect. Int J Cardiol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29996977
Pharmacists aid to find statin eligible diabetic patients
The role of pharmacists to help improve the pharmacological management of patients with increased CVD risk is, gaining importance. Their electronic medication records can be sourced to flag patient that are not using appropriate drugs based on concomitant medication. Using a pharmacist’s intervention workflow model and screening algorithm patients with diabetes were monitored for statin use. The study endpoints were the percentage of patients identified and the number of patients that started statin prescriptions. There were 103 diabetic patients not using statins when the study started. After 90-days 30 (29.1%) patients were identified based on the workflow initiation. From these identified patients, 12 (40%) gave verbal consent that allowed the pharmacist to intervene with their health care provider and 7 (58.3%) were given a statin prescription. This study showed the potential role of community pharmacists to improve CVD risk management in diabetic patients.
Drake ES, Harris DK, Marciniak MW. Community pharmacist-led intervention to identify persons with diabetes not on statin therapy. Journal of the American Pharmacists Association : JAPhA 2018; 58:S125-s130. http://www.ncbi.nlm.nih.gov/pubmed/?term=30006183
Addressing increased VTE risk in renal patients - statins can help
In recent years a fairly strong relationship with chronic kidney disease (CKD) and the development of venous thromboembolism (VTE) was noted. Although the reasons for this are not clear, exposure to increased pro-coagulant and inflammatory markers, frequently observed in CKD patients, are likely to be relevant, as well as yet to be determined risk factors. In this study the authors set out to examine if factors associated with increased or reduced VTE risk in the general population, would have comparable consequences in CKD patients. Data collected in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a prospective cohort study of self-reported blacks and whites US resident, was used. A case – control cohort matching was performed for 294 VTE cases and 939 controls. HR’s were calculated for several biomarkers and VTE risk factors. A 10 mL /min-/11.73 m-2 eGFR decrease was associated with a HR 1.13 (5-100) Risk for VTE was attenuated for each SD increase of D-dimer, HR 1.69 (1.41–2.02); factor VIII HR 2.23 (1.89–2.62) and hsCRP HR 1.29 (1.09–1.52). Normal BMI reduced risk by 50% but only in non-CKD patients, statin use HR 0.68 (0.50–0.93), physical activity, and warfarin use reduced VTE risk in patients with and without CKD. In patients with impaired renal function, eGFR is inversely associated with inflammatory and procoagulant markers and these may mediate the observed increased risk of VTE in CKD patients. this risk was eased in patients with high physical activity, that used warfarin or statins.
Cheung KL, Zakai NA, Callas PW et al. Mechanisms and mitigating factors for venous thromboembolism in chronic kidney disease: the REGARDS Study. Journal of thrombosis and haemostasis : JTH 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29984467
Relevant publications
  1. Tokuhisa H, Murai H, Okabe Y et al. Differential effects of lipophilic and hydrophilic statins on muscle sympathetic nerve activity in heart failure with preserved left ventricular ejection fraction. Autonomic neuroscience : basic & clinical 2018; 213:8-14. http://www.ncbi.nlm.nih.gov/pubmed/?term=30005743
  2. Shahreyar M, Salem SA, Nayyar M et al. Hyperlipidemia: Management with Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors. Journal of the American Board of Family Medicine : JABFM 2018; 31:628-634. http://www.ncbi.nlm.nih.gov/pubmed/?term=29986989
  3. Ricci G, Ciccone MM, Giordano P, Cortese F. Statins: pharmacokinetics, pharmacodynamics, and cost-effectiveness analysis. Current vascular pharmacology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29984667
  4. Ozaki Y, Tanaka A, Nishiguchi T et al. High-density lipoprotein cholesterol as a therapeutic target for residual risk in patients with acute coronary syndrome. PLoS One 2018; 13:e0200383. http://www.ncbi.nlm.nih.gov/pubmed/?term=29995934
  5. Ji T, Zhao Y, Wang J et al. Effect of Low-Dose Statins and Apolipoprotein E Genotype on Cerebral Small Vessel Disease in Older Hypertensive Patients: A Subgroup Analysis of a Randomized Clinical Trial. Journal of the American Medical Directors Association 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30006015
  6. Cofan M, Ros E. Use of plant sterol and stanol fortified foods in clinical practice. Curr Med Chem 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29984649
  7. Zhou L, Liu X, Wang ZQ et al. Simvastatin Treatment Protects Myocardium in Non-coronary Artery Cardiac Surgery by Inhibiting Apoptosis Through miR-15a-5p Targeting. Journal of cardiovascular pharmacology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29985281
  8. Thompson W, Pottegard A, Nielsen JB et al. How Common is Statin Use in the Oldest Old? Drugs Aging 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29987758
  9. Ofori-Asenso R, Ilomaki J, Tacey M et al. Prevalence and Incidence of Statin Use and 3-Year Adherence and Discontinuation Rates Among Older Adults With Dementia. American journal of Alzheimer's disease and other dementias 2018:1533317518787314. http://www.ncbi.nlm.nih.gov/pubmed/?term=29991271
  10. Naumovska Z, Nestorovska AK, Grozdanova A et al. Evaluation of statin utilization in the Republic of Macedonia during 2013-2016. Clinicoecon Outcomes Res 2018; 10:339-347. http://www.ncbi.nlm.nih.gov/pubmed/?term=29983582
  11. Marques AC, Busanello ENB, de Oliveira DN et al. Coenzyme Q10 or Creatine Counteract Pravastatin-Induced Liver Redox Changes in Hypercholesterolemic Mice. Frontiers in pharmacology 2018; 9:685. http://www.ncbi.nlm.nih.gov/pubmed/?term=29997512
  12. Lin SM, Wang JH, Liang CC, Huang HK. Statin use is associated with decreased osteoporosis and fracture risks in stroke patients. J Clin Endocrinol Metab 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29982482
  13. Fan Y, Jin X, Man C, Gong D. Does Adjuvant Treatment With Ginkgo Biloba to Statins Have Additional Benefits in Patients With Dyslipidemia? Frontiers in pharmacology 2018; 9:659. http://www.ncbi.nlm.nih.gov/pubmed/?term=29988404
  14. Danielak D, Karazniewicz-Lada M, Glowka F. Assessment of the Risk of Rhabdomyolysis and Myopathy During Concomitant Treatment with Ticagrelor and Statins. Drugs 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30003466
  15. Akinwunmi B, Vitonis AF, Titus L et al. Statin Therapy and Association with Ovarian Cancer risk in the New England Case Control (NEC) Study. International journal of cancer. Journal international du cancer 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30006925
  16. Pravastatin. In: Drugs and Lactation Database (LactMed). Bethesda (MD): National Library of Medicine (US); 2006.
  17. Lovastatin. In: Drugs and Lactation Database (LactMed). Bethesda (MD): National Library of Medicine (US); 2006.
  18. Fluvastatin. In: Drugs and Lactation Database (LactMed). Bethesda (MD): National Library of Medicine (US); 2006.
  19. Simvastatin. In: Drugs and Lactation Database (LactMed). Bethesda (MD): National Library of Medicine (US); 2006.
  20. Atorvastatin. In: Drugs and Lactation Database (LactMed). Bethesda (MD): National Library of Medicine (US); 2006.
  21. Rosuvastatin. In: Drugs and Lactation Database (LactMed). Bethesda (MD): National Library of Medicine (US); 2006.
  22. Ezetimibe. In: Drugs and Lactation Database (LactMed). Bethesda (MD): National Library of Medicine (US); 2006.
Miscellaneous publications
  1. Turner RM, Fontana V, Bayliss M et al. Development, validation and application of a novel HPLC-MS/MS method for the quantification of atorvastatin, bisoprolol and clopidogrel in a large cardiovascular patient cohort. Journal of pharmaceutical and biomedical analysis 2018; 159:272-281. http://www.ncbi.nlm.nih.gov/pubmed/?term=30005242
  2. Rakhmatia YD, Ayukawa Y, Furuhashi A, Koyano K. Carbonate Apatite Containing Statin Enhances Bone Formation in Healing Incisal Extraction Sockets in Rats. Materials (Basel, Switzerland) 2018; 11. http://www.ncbi.nlm.nih.gov/pubmed/?term=30002343
  3. Araujo-Lima CF, Peres RB, Silva PB et al. Repurposing strategy of atorvastatin against Trypanosoma cruzi: in vitro monotherapy and combined therapy with benznidazole exhibits synergistic trypanocidal activity. Antimicrobial agents and chemotherapy 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29987140
  4. Abd-Elsalam WH, El-Helaly SN, Ahmed MA, Al-Mahallawi AM. Preparation of novel phospholipid-based sonocomplexes for improved intestinal permeability of rosuvastatin: In vitro characterization, dynamic simulation, Caco-2 cell line permeation and in vivo assessment studies. Int J Pharm 2018; 548:375-384. http://www.ncbi.nlm.nih.gov/pubmed/?term=29991454
  5. Alshora DH, Ibrahim MA, Elzayat E et al. Rosuvastatin calcium nanoparticles: Improving bioavailability by formulation and stabilization codesign. PLoS One 2018; 13:e0200218. http://www.ncbi.nlm.nih.gov/pubmed/?term=29985967
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