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Update - Week 07 -  2019
 
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

Harms or benefits of statin in the elderly?
Should elderly (>75years) be treated with statins? A question still shrouded in controversies, largely because only a single trial, the PROSPER study, was designed to study this therapeutic dilemma. The HOPE-3 trial, that included aging patients as well, did not show improvements in the elderly participants. In this recent Cholesterol Treatment Trialist (CTT) meta-analysis, the latest attempt to shed light on this frequently encountered treatment dilemma. Based on data collected in no less than 28 statin trials (N=134 537!), using individual patient data of statin vs controls as well as five studies (N=39 612) that compared high dose vs low dose statin. Patients were subdivided in 6 age groups. The oldest patients were >75 years at randomization (N= 14 483 / 8%). After a median follow-up time of 4.9 years, and per 1 mmol/l LDL-c reduction, a relative risk reduction of 21% (RR 0·79, 95% CI 0·77–0·81) for MACE was detected. Patients receiving a higher dosage vs lower dosage the MACE risk was reduced by 24% (RR 0·76, 95% CI 0·73–0·79) This difference remained significant in all age categories but there was a trend towards lessened proportional risk reduction in the older age groups. Sub-analyses that focused on coronary revascularization and stroke showed similar benefits in all age groups as well. The risk-modifying effects were comparable in all age categories in patients with pre-existing vascular disease. However, the protective effects of statins in elderly patients without ASCVD were less prominent with advancing age. Re-assuring, especially for those that remain critical regarding statins safety in elderly patients, no deleterious effect at any age on non-vascular mortality, cancer death, or cancer incidence, were noted. Overall the results of this meta-analysis support the use of statins in elderly patients with ASCVD, even in those >75 years. For a primary prevention indication of statin in the very elderly current data is insufficient, however, the ongoing Australian STAREE (N=22 000) trial will help to address these issues as well, the completion date of this study is estimated in 2022.
Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomized controlled trials. Lancet 2019; 393:407-415. http://www.ncbi.nlm.nih.gov/pubmed/?term=30712900
Cheung BMY, Lam KSL. Never too old for statin treatment? Lancet 2019; 393:379-380. http://www.ncbi.nlm.nih.gov/pubmed/?term=30712888
 
Stopping statins has consequences, and these are not good!
One of the common questions asked at lectures or conferences is: when can patients stop statins? The answer is: Never! There is a false sense of assurance when patients reach an LDL-c target for a  limited period of time, that somehow tempts doctors to think that patients can manage their LDL-c without needing medication. The consequences of stopping statins are ominous and best illustrated when comparing the adherent patient with those that are non-adherent. In this analysis of the US Veterans Affairs Health Care system, patients (21-85 years) with CHD and using statins were evaluated for all-cause mortality. Of note included patients had been using stable statin dosages for a mean period of 3 -years and this is in sharp contrast of studies that evaluated patients with first statin prescriptions. Between January 2013 and April 2014, 347 104 eligible patients were included. Adherence was better in patients that used moderate intensity statins compared to high-intensity statins, OR: 1.18 (1.16-1.20). Less adherent as well were women, minority groups and younger- & older patients (reference age 65-74). The total number of deaths over the 2.9-year follow-up was 85 930 (24.8%). Patients with a medication possession ratio (MPR) of >90% compared to patients with an MPR < 50% had a corrected mortality HR of 1.30 (1.27-1.34). with an MPR 50%-69%; HR: 1.21 (1.118-1.24) and an MPR 70-89%; HR1.08 (1.06-1.09). Patients that were less adherent to high-intensity statins suffered the largest impact on mortality. The authors cautioned that that statin adherence in secondary preventions should not be taken for granted, even in patients that used statin for a longer period of time.
Rodriguez F, Maron DJ, Knowles JW et al. Association of Statin Adherence With Mortality in Patients With Atherosclerotic Cardiovascular Disease. JAMA cardiology 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30758506
 
Can statins reduce fitness and impair physical activity?
The prevailing sentiment of omnipresent statin-related debilitating muscle side effects seems to be refuted by this intriguing meta-analysis on the effect of statins on physical activity. Studies that evaluated parameters of physical activity or fitness by comparing statin users with patients not using statins, did not show a significantly worse outcome in statin users. Included in the meta-analysis were 16 RCT’s (N=2 944) in which statins were compared to placebo. Physical fitness was determined and compared by measuring maximal exercise time and maximal heart rate, in some type of exercise testing. Insufficient data were available for habitual physical activity, or fitness. No significant differences between statin users and controls for heart rate: 1.8 bpm (-7.4-13; p=0.59) and exercise time 82.8seconds (-31.9-197.4; p=0.516) were observed.  Out of the 16 included studies, 6 trials even showed a significantly improved physical activity levels in statin users! Two trials studied physical activity levels, one self-reported and one used an accelerometer. Neither trials were able to discern differences in physical activity between the statin users and controls. Walking distance was studied in four trials. Two trials reported improved walking distance in statin users while no improvement was noted in the placebo group. In the two remaining studies, no difference between the two treatment arms was noted. Despite the limited availability of trials that studied physical activity, this meta-analysis reconfirms the absence of detrimental effects of statins on muscle related physical activity. The authors emphasize that their data should re-assure patients that statins do not negatively impact physical activity or fitness however to confirm these observations, future statin trials should incorporate measures of physical activity and fitness.
Gadowski A, Owen AJ, Curtis A et al. The Effects of Statins on Physical Activity or Physical Fitness Among Adults: A Systematic Review and Meta-Analysis of Randomised Controlled Trials. Journal of aging and physical activity 2019:1-37. http://www.ncbi.nlm.nih.gov/pubmed/?term=30747563

Atorvastatin reduced bleeding complications after aortic valve surgery
The effects of statins beyond lowering LDL-cholesterol was evaluated in this retrospective cohort study in patients (N=1 145) that had elective primary isolated aortic valve replacement between January 2009 and December 2017; 548 patients used atorvastatin and 598 were in the control group. The objective was to evaluate bleeding complications and use of blood products. In earlier post cardiac surgery studies, beneficial effects on these parameters were observed. In this cohort bleeding complications, 12 hrs. post-surgery were significantly reduced; 372 ± 137 vs 561 ± 219 ml; P = 0.001. Similar benefits for overall bleeds; 678 ± 387 vs 981 ± 345 ml, P = 0.001). Use of packed red blood cells was lower in patients that received atorvastatin; 26.3% vs 32.3% of the controls (P = 0.027). No difference in surgical complications between the two groups but the length of hospital stay was of shorter duration as well, 6.0 ± 1.4 vs 6.9 ± 2.1 days (P = 0.001). Patients using a lower dosage compared to a higher dosage of atorvastatin experienced 20% more postoperative bleeding complications (P=0.001). The results from this retrospective analysis confirm the benefits of pre-surgical treatment with atorvastatin. Reduced post-op bleedings, as well as the need for packed red cells, in patients scheduled for elective isolated aortic valve replacements. Ultimately this would impact the recovery period and hospitalization costs as well.
Nenna A, Spadaccio C, Lusini M et al. Preoperative atorvastatin reduces bleeding and blood transfusions in patients undergoing elective isolated aortic valve replacement. Interact Cardiovasc Thorac Surg 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30753487
 
OMT in discharged Chinese ACS patients improved outcomes and reduced costs
This Chinese study examined the impact of optimal medical therapy (OMT) in discharged ACS patient. A retrospective analysis of the Tianjin Urban Employee Basic Medical Insurance database (2011-2015). OMT was defined as the use of the following medications: antiplatelets, b-blockers, ACEIs/ARBs, and statins. The endpoints studies were all-cause and ACS-related health care resource utilization as well as direct medical costs. There were 22 041 patients included, only 3 336 (15.1%) were discharged with OMT. Hospitalizations were reduced in the OMT cohort compared to the non-OMT patients (38.1% vs 43.2%; P < 0.001) as well as fewer hospitalizations (1.55 vs 1.64; P = 0.019) and shorter annualized length of stay (15.9 vs 17.2 d; P = 0.041). For 2014 the costs of patient-related resources, after discharge, were significantly lower in OMT patients (1USD = 6.20 Chinese yuan [CNY]). Outpatients services, 9 958 vs 10 060 CNY (P = 0.006); adjusted difference, +456 CNY (P = 0.004).  All-cause total costs 20 771 vs 22 877 CNY (P = 0.174); adjusted difference, -2089 CNY [P = 0.006]). The major contributor was lower costs for inpatient services 10 813 vs 12 817 CNY (P < 0.001); adjusted difference, -2 184 CNY [P = 0.001]). The
difference in ACS-related total costs were not statistically significant 8 535 vs 9 304 CNY (P = 0.128); adjusted difference, -558 CNY (P = 0.214). Noteworthy are the low rates of OMT in the discharged ACS patients as well as the reduced hospitalizations and lower directly related all-cause medical costs in the patients that were treated with OMT. The authors commented on developing strategies to improve OMT in discharged ACS patients to not only improve outcomes but reduce costs as well.
He X, Wang Y, Cong H et al. Impact of Optimal Medical Therapy at Discharge on 1-year Direct Medical Costs in Patients with Acute Coronary Syndromes: A Retrospective, Observational Database Analysis in China. Clinical therapeutics 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30770126
 
 
Relevant publications
  1. Khan SU, Khan MU, Rahman H et al. A Bayesian network meta-analysis of preventive strategies for contrast-induced nephropathy after cardiac catheterization. Cardiovascular revascularization medicine : including molecular interventions 2019; 20:29-37. http://www.ncbi.nlm.nih.gov/pubmed/?term=30757995
  2. Kang DO, Park Y, Seo JH et al. Time-dependent prognostic effect of high sensitivity C-reactive protein with statin therapy in acute myocardial infarction. J Cardiol 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30745001
  3. Sharpton RA, Laucka PJ, McKeller RN et al. The Impact of Obesity on the Efficacy of Simvastatin for Lowering Low-Density Lipoprotein Cholesterol in a Veteran Population. Federal practitioner : for the health care professionals of the VA, DoD, and PHS 2017; 34:41-44. http://www.ncbi.nlm.nih.gov/pubmed/?term=30766266
  4. Sharma A, Sun JL, Lokhnygina Y et al. Patient Phenotypes, Cardiovascular Risk, and Ezetimibe Treatment in Patients After Acute Coronary Syndromes (from IMPROVE-IT). Am J Cardiol 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30739657
  5. Shapiro MD, Minnier J, Tavori H et al. Relationship Between Low-Density Lipoprotein Cholesterol and Lipoprotein(a) Lowering in Response to PCSK9 Inhibition With Evolocumab. J Am Heart Assoc 2019; 8:e010932. http://www.ncbi.nlm.nih.gov/pubmed/?term=30755061
  6. Masajtis-Zagajewska A, Nowicki M. Effect of atorvastatin on iron metabolism regulation in patients with chronic kidney disease - a randomized double blind crossover study. Ren Fail 2018; 40:700-709. http://www.ncbi.nlm.nih.gov/pubmed/?term=30741616
  7. Li B, Salata K, de Mestral C et al. Perceptions of Canadian vascular surgeons toward pharmacologic risk reduction in patients with peripheral artery disease: 2018 update. Annals of vascular surgery 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30771465
  8. Joshi SS, Ruth K, Smaldone MC et al. Perioperative Statin Use and Acute Kidney Injury in Patients Undergoing Partial Nephrectomy. Kidney cancer 2018; 2:47-55. http://www.ncbi.nlm.nih.gov/pubmed/?term=30740579
  9. Ho BL, Lin YJ, Lin SF et al. Statins and the risk of bleeding in patients taking dabigatran. Acta neurologica Scandinavica 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30742307
  10. Fan L, Wang Y, Liu X, Guan X. Association between statin use and herpes zoster: systematic review and meta-analysis. BMJ Open 2019; 9:e022897. http://www.ncbi.nlm.nih.gov/pubmed/?term=30765397
  11. Drake B, Grimm DL, Allman J, 2nd. Treatment Failure With Atorvastatin After Change From Rosuvastatin to Atorvastatin. Federal practitioner : for the health care professionals of the VA, DoD, and PHS 2015; 32:25-29. http://www.ncbi.nlm.nih.gov/pubmed/?term=30766036
  12. Dowd CM, Tillmann JJ. Therapeutic Interchange From Rosuvastatin to Atorvastatin in a Veteran Population. Federal practitioner : for the health care professionals of the VA, DoD, and PHS 2015; 32:20-24. http://www.ncbi.nlm.nih.gov/pubmed/?term=30766035
  13. Bentz AJ, Netland PJ, Newman WP et al. Comparison of Cardiovascular Outcomes Between Statin Monotherapy and Fish Oil and Statin Combination Therapy in a Veteran Population. Federal practitioner : for the health care professionals of the VA, DoD, and PHS 2018; 35:26-31. http://www.ncbi.nlm.nih.gov/pubmed/?term=30766323
  14. Altunkeser BB, Tuncez A, Ozturk B et al. Comparative effects of high-dose atorvastatin versus rosuvastatin on lipid parameters, oxidized low-density lipoprotein, and proprotein convertase subtilisin kexin 9 in acute coronary syndrome. Coronary artery disease 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30741744
  15. Al'Aref SJ, Su A, Gransar H et al. A cross-sectional survey of coronary plaque composition in individuals on non-statin lipid lowering drug therapies and undergoing coronary computed tomography angiography. Journal of cardiovascular computed tomography 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30745132
  16. Wang X, Luo S, Gan X et al. Safety and efficacy of ETC-1002 in hypercholesterolemic patients: a meta-analysis of randomized controlled trials. Kardiol Pol 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30740643
  17. Vesza Z, Pires C, da Silva PM. Statin-related Lichenoid Dermatosis: An Uncommon Adverse Reaction to a Common Treatment. European journal of case reports in internal medicine 2018; 5:000844. http://www.ncbi.nlm.nih.gov/pubmed/?term=30756034
  18. Trong HN, Tat TN, Anh TTN et al. Efficacy of Adding Oral Simvastatin to Topical Therapy for Treatment of Psoriasis: The Vietnamese Experience. Open access Macedonian journal of medical sciences 2019; 7:237-242. http://www.ncbi.nlm.nih.gov/pubmed/?term=30745969
  19. Petrov I, Dumitrescu A, Snejdrlova M et al. Clinical Management of High and Very High Risk Patients with Hyperlipidaemia in Central and Eastern Europe: An Observational Study. Adv Ther 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30758746
  20. Padegimas A, Clasen S, Ky B. Cardioprotective strategies to prevent breast cancer therapy-induced cardiotoxicity. Trends Cardiovasc Med 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30745071
  21. Nishikido T, Ray KK. Non-antibody Approaches to Proprotein Convertase Subtilisin Kexin 9 Inhibition: siRNA, Antisense Oligonucleotides, Adnectins, Vaccination, and New Attempts at Small-Molecule Inhibitors Based on New Discoveries. Frontiers in cardiovascular medicine 2018; 5:199. http://www.ncbi.nlm.nih.gov/pubmed/?term=30761308
  22. Murtola TJ, Syvala H, Riikonen J. Reply to Jae Heon Kim and Benjamin I. Chung's Letter to the Editor re: Teemu J. Murtola, Heimo Syvala, Teemu Tolonen, et al. Atorvastatin Versus Placebo for Prostate Cancer Before Radical Prostatectomy-A Randomized, Double-blind, Placebo-controlled Clinical Trial. Eur Urol 2018;74:697-701. European urology 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30738709
  23. Marcum ZA, Walker RL, Jones BL et al. Patterns of antihypertensive and statin adherence prior to dementia: findings from the adult changes in thought study. BMC geriatrics 2019; 19:41. http://www.ncbi.nlm.nih.gov/pubmed/?term=30764775
  24. Marco-Benedi V, Jarauta E, Perez-Calahorra S et al. Treatment of a high cardiovascular risk patient with McArdle's disease with PCSK9 inhibitors. Clin Investig Arterioscler 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30738610
  25. Kim JH, Chung BI. Re: Timu J. Murtola, Hemo Syvala, Teemu Tolonen, et al. Atorvastatin Versus Placebo for Prostate Cancer Before Radical Prostatectomy-A Randomized, Double-blind, Placebo-controlled Clinical Trial. Eur Urol 2018;74:697-701. European urology 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30738708
  26. Husain MI, Chaudhry IB, Khoso AB et al. Adjunctive simvastatin for treatment-resistant depression: study protocol of a 12-week randomised controlled trial. BJPsych open 2019; 5:e13. http://www.ncbi.nlm.nih.gov/pubmed/?term=30762508
  27. Garcia R, Burkle J. New and Future Parenteral Therapies for the Management of Lipid Disorders. Arch Med Res 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30739730
  28. Del Vecchio L, Baragetti I, Locatelli F. New agents to reduce cholesterol levels: implications for nephrologists. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30753594
  29. Colantonio LD, Monda KL, Rosenson RS et al. Characteristics and Cardiovascular Disease Event Rates among African Americans and Whites Who Meet the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) Trial Inclusion Criteria. Cardiovasc Drugs Ther 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30746585
  30. Calvillo-Arguelles O, Abdel-Qadir H, Michalowska M et al. Cardioprotective Effect of Statins in Patients With HER2-Positive Breast Cancer Receiving Trastuzumab Therapy. Can J Cardiol 2019; 35:153-159. http://www.ncbi.nlm.nih.gov/pubmed/?term=30760421
Basic Science publications
 
 
  1. Lee S, Lee HJ, Kang H et al. Trastuzumab Induced Chemobrain, Atorvastatin Rescued Chemobrain with Enhanced Anticancer Effect and without Hair Loss-Side Effect. Journal of clinical medicine 2019; 8. http://www.ncbi.nlm.nih.gov/pubmed/?term=30754707
  2. Lee S, Kim DH, Youn YN et al. Rosuvastatin attenuates bioprosthetic heart valve calcification. The Journal of thoracic and cardiovascular surgery 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30738596
  3. Harshman SG, Shea MK, Fu X et al. Atorvastatin Decreases Renal Menaquinone-4 Formation in C57BL/6 Male Mice. The Journal of nutrition 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30753659
  4. Han Q, Liu Q, Zhang H et al. Simvastatin Improves Cardiac Hypertrophy in Diabetic Rats by Attenuation of Oxidative Stress and Inflammation Induced by Calpain-1-Mediated Activation of Nuclear Factor-kappaB (NF-kappaB). Medical science monitor : international medical journal of experimental and clinical research 2019; 25:1232-1241. http://www.ncbi.nlm.nih.gov/pubmed/?term=30767945
  5. Zaki Husain Rizvi S, Ali Shah F, Khan N et al. Simvastatin-loaded solid lipid nanoparticles for enhanced anti-hyperlipidemic activity in hyperlipidemia animal model. Int J Pharm 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30753932
  6. Rosales-Acosta B, Mendieta A, Zuniga C et al. Simvastatin and other inhibitors of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase of Ustilago maydis (Um-Hmgr) affect the viability of the fungus, its synthesis of sterols and mating. Revista iberoamericana de micologia 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30745018
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