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Update - Week 40,  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

Polypill regimen outperforms usual care in CVD risk factor management
The Polypill strategy has been evaluated in numerous trials. In the SPCAE collaboration three Polypill trials, examining the effects of usual cared vs a Polypill based regime in high risk patients, were combined. The individual data of 3 140 participants were evaluated. Baseline medication use was categorized by statin potency and number of blood pressure medications. Adherence to anti platelet medication as well as systolic blood pressure (SBP) and LDL-cholesterol, stratified by baseline medication strength, was assessed. The evaluation after 12 months showed that patients using the Polypill regimen had improved SBP. This difference varied according to the BP treatment at baseline: -3.3, -5.9, -2.5 and +1 mm Hg for patient using 0,1,2 and 3+ BP lowering medications. Similarly, plasma LDL-cholesterol concentration was lower in the Polypill users as well. For patients who at baseline were not on statins, used less potent statins or were taking equipotent statins, the LDL-c concentrations were – 0.21 mmol/L, - 0.16 mmol/L and – 0,14 mmol/L lower respectively. The authors concluded that improved adherence to the Polypill regimen offset the reduced potency of the separate components used at baseline. This ultimately results in improved control of multiple risk factors in high CVD risk patients.   
Webster R, Bullen C, Patel A et al. Impact of switching to polypill based therapy by baseline potency of medication: Post-hoc analysis of the SPACE Collaboration dataset. Int J Cardiol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28986058
 
Comparing efficacy of PCSK9ab in patients on maximum tolerated statins
In this network, meta-analysis of 15 selected published trials were alirocumab, evolocumab, ezetimibe or placebo were added to maximum tolerated statin therapy were compared. Overall PCSK9ab reduced LDL-c by 54% -74% when compared to placebo and 26%-46%, compared to ezetimibe. The authors conclude that evolocumab had a superior LDL-c lowering effect compared to alirocumab. Evolocumab 140 mg every 2 weeks reduced LDL-C by 74% versus placebo and 46% versus ezetimibe; alirocumab 75 mg every 2 weeks, 54% and 26%; alirocumab 150 mg every 2 weeks, 60% and 32% respectively; evolocumab 420 mg every month, 72% and 48%; and alirocumab 300 mg every month, 52% and 28%. This is an intriguing observation because the dose finding studies for both agents showed very similar LDL-c lowering effects. Administering PCSK9 antibodies neutralizes all circulating anti-bodies. PCSK9 + PCSK9ab complexes are removed from the plasma by exactly the same biological mechanisms. In contrast with small molecules, anti-bodies are not prone to pharmaco dynamic – kinetic interactions that can cause efficacy heterogeneity of different molecules that share the same drug target. Differences in LDL-C lowering effects, reflected in waterfall plots, show that some patients have reduced response and even non-responders were discovered in PCSK9ab trials. However these differences are most likely related to patient specific characteristics and not by differences in the ant-bodies persé. The reduced efficacy observed in the SPIRE trials of bococizumab was caused by an increased immunogenicity and subsequent formation of anti-bodies against bococizumab. The conclusion that  evolocumab has superior potency, compared to alirocumab, is premature. Patient characteristics play an important role that that cannot be adequately addressed using this type of analysis. Only a direct comparison of PCSK9ab in a randomized cross over designed trial will be able to show if there are significant differences in LDL-C lowering potency between the two PCSK9ab.  
Toth PP, Worthy G, Gandra SR et al. Systematic Review and Network Meta-Analysis on the Efficacy of Evolocumab and Other Therapies for the Management of Lipid Levels in Hyperlipidemia. J Am Heart Assoc 2017; 6. http://www.ncbi.nlm.nih.gov/pubmed/?term=28971955
 
Do statins benefit dialysis patients after an AMI?
Although previous large randomized placebo controlled trials showed no benefit of rosuvastatin or atorvastatin administered to dialysis patients, the question if dialysis patients after an MI should be treated with statins has not been addressed. The authors used the Taiwanese National Health Insurance database to evaluate dialysis patients that were hospitalized for an AMI. Statin users were compared with no statin use after 1:1 propensity score matching. In total 790 patients were using statin and 1788 patients did not. The patients were followed for four years to determine differences in clinical outcome. Statin benefits were observed after one year up until the end of the follow up period. Of the statin users 22.9% vs 31.1% of the no statin users died within a year. HR: 0.70 (0.58-0.85). After 4 years 48% vs 55.1% did not survive. HR: 0.76 (0.67-0.88). No difference in cardiovascular outcomes or adverse events, e.g. myopathy and new onset diabetes, were observed. The authors concluded that moderate to high doses statins might lower mortality in dialysis patients when using statins after an AMI despite that no difference was observed in cardiovascular outcomes. The retrospective observational nature of the study would require well designed randomized trials to confirm these observations.
Chung CM, Lin MS, Chang CH et al. Moderate to high intensity statin in dialysis patients after acute myocardial infarction: A national cohort study in Asia. Atherosclerosis 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28985950
 
Myopathy in pediatric FH patients is rare but can occur
In this case report pediatricians from Rome, Italy share their experience of statin safety in children. They report on 122 FH children (6-18 years) that have been treated with statins for a median period of 29 months. One patient a 10-year-old boy developed severe myalgia, muscle weakness and darkened urine, 10 days after starting treatment with atorvastatin 10 mg. CK and Myoglobin were severely elevated 1951 UI/L and 122.64 ng/mL respectively, indicative of rhabdomyolysis. After fluid therapy and stopping atorvastatin, a complete clinical recovery was observed. The authors stress that in children using statin baseline CK levels are of limited usefulness to predict rhabdomyolysis. Health care professionals need to alert caretakers and young FH patients to recognize the classical symptoms of myositis and rhabdomyolysis, in order to intervene before serious renal damage has occurred.
Buonuomo PS, Macchiaiolo M, Mastrogiorgio G et al. Statin-associated myopathy in pediatric settings: Myth or fact? J Pediatr 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28964429
 
Reduction of ischemic stroke in IMPROVE–IT
In the IMPROVE-IT study 18 144 high risk post ACS patients were randomized to simvastatin + ezetimibe or simvastatin + placebo. The addition of ezetimibe not only lowered LDL-c by 17.7mg/dl,at 1 year, but also reduced the primary endpoint by 7.6% (absolute risk reduction of 2.3%) after 6 years of treatment. In this sub analysis, the benefits of adding ezetimibe to simvastatin were evaluated for the prevention of stroke, with special emphasis on patients with a prior stroke. Overall 641 patients (3.5%) experienced at least one stroke during the study, the majority (82%) were ischemic strokes. A non-significant reduction of first stroke of any etiology HR 0.86 (0.73-1.00) was noted. For ischemic cerebrovascular events the addition of ezetimibe showed a significant 21% reduction, HR:0.79 (67-0.94; P=0.008). Hemorrhagic strokes increased non-significantly, HR:1.38 (0.93-2.04; P=0.11). Analysis of total events, including first stroke and recurrent strokes, resulted in a significant reduction of 17%, HR 0.83 (0.70-0.89; P=0.029). For ischemic strokes only a significant 24% lower event rate was observed, HR 0.83 (0.70-0.98; P=0.003). Patients that suffered a stroke prior to entering the study experienced a higher risk and also a larger reduction risk for a subsequent stroke. For all strokes combined a significant 40% lower risk was observed, HR: 0.60 (0.38-0.95; p=0.030). An absolute risk reduction of 8.6% resulting in a NNT of 12. For ischemic stroke a significant 48% relative risk reduction was noted, HR 0.52 (0.31-0.86; P=0.011). The absolute risk was reduced by 7.6% translating in a NNT of 13. The authors concluded that adding ezetimibe to simvastatin in stable ACS patients reduces the incidence or stroke and recurrent stroke, especially in patients that suffered a prior stroke.  
Bohula EA, Wiviott SD, Giugliano RP et al. Prevention of Stroke with the Addition of Ezetimibe to Statin Therapy in Patients with Acute Coronary Syndrome in IMPROVE-IT. Circulation 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28972004
 
 
CVD risk score predominantly determines statin initiation by New Zealand primary care physicians
In this New Zealand study the aimed to examine how clinicians use and implement guideline recommendations. The observed a cohort of 76 571 patients (aged 35-75 years), not using statins but their risk was calculated using a modified Framingham risk score adjusted for the New Zealand population. Patients ware under the care of their primary care physician. This cohort was followed for 6 months to determine which patients initiated statins. Their CVD risk was assessed between July 2007 and June 2011. Based on National Guideline recommendations patients that were eligible for statins were queried. Althouhg statin were prescribed more frequently in patients with a higher risk, there was not a sharp increase at treatment thresholds of 15% and 20% 10-year CVD risk (P=0.314 and P=0.731). the risk score was a better predictor for statin initiation than the measured lipid values(Area Under the Curve 0.725 vs 0.682). The primary care physicians decision to start statin was based on a number of other factors. The authors concluded that in New Zealand primary care physicians use predicted CVD risk in order to decide if patients should start with statins. Other factors are associated with statin dispensing that are unrelated to the CVD risk score.
Robinson T, Jackson R, Wells S et al. An observational study of how clinicians use cardiovascular risk assessment to inform statin prescribing decisions. The New Zealand medical journal 2017; 130:28-38. http://www.ncbi.nlm.nih.gov/pubmed/?term=28981492
Relevant publications
  1. Williams SA, Murthy AC, DeLisle RK et al. Improving Assessment of Drug Safety Through Proteomics: Early Detection and Mechanistic Characterization of the Unforeseen Harmful Effects of Torcetrapib. Circulation 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28974520
  2. van Giessen A, de Wit GA, Moons KGM et al. Rethinking optimization methods identified optimal risk thresholds for preventive treatment: an illustration in coronary heart disease. J Clin Epidemiol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28986242
  3. Tulbah AS, Pisano E, Scalia S et al. Inhaled simvastatin nanoparticles for inflammatory lung disease. Nanomedicine (Lond) 2017; 12:2471-2485. http://www.ncbi.nlm.nih.gov/pubmed/?term=28972463
  4. Smit J, Lopez-Cortes LE, Thomsen RW et al. Statin Use and Risk of Community-Acquired Staphylococcus aureus Bacteremia: A Population-Based Case-Control Study. Mayo Clinic proceedings 2017; 92:1469-1478. http://www.ncbi.nlm.nih.gov/pubmed/?term=28982483
  5. Schils E. [Lipid-lowering therapy in the elderly]. Revue medicale de Bruxelles 2017; 38:363-365. http://www.ncbi.nlm.nih.gov/pubmed/?term=28981241
  6. Rosenson RS, Larrey D, Waters DD, Olsson AG. RE: Praluent (Alirocumab)-Induced Renal Injury. Journal of pharmacy practice 2017:897190017734429. http://www.ncbi.nlm.nih.gov/pubmed/?term=28974137
  7. Kilic S, Sumerkan MC, Emren V et al. Secondary prevention of coronary heart disease in elderly population of turkey: A subgroup analysis of ELDERTURK study. Cardiology journal 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28980279
  8. Hu X, Cheng J, Li C. Effects of rosuvastatin and atorvastatin on nonsustained ventricular tachycardia in patients with ST-elevation myocardial infarction: a retrospective analysis. Eur J Clin Pharmacol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28965256
  9. Grudzinska FS, Dosanjh DP, Parekh D et al. Statin therapy in patients with community-acquired pneumonia. Clinical medicine (London, England) 2017; 17:403-407. http://www.ncbi.nlm.nih.gov/pubmed/?term=28974587
  10. Bergland Ellingsen S, Nordmo E, Tore Lappegard K. Recurrence and Severe Worsening of Hepatotoxicity After Reintroduction of Atorvastatin in Combination With Ezetimibe. Clinical medicine insights. Case reports 2017; 10:1179547617731375. http://www.ncbi.nlm.nih.gov/pubmed/?term=28979175
  11. Balkanay OO, Omeroglu SN. [Approach to peripheral arterial disease in the elderly]. Turk Kardiyoloji Dernegi arsivi : Turk Kardiyoloji Derneginin yayin organidir 2017; 45:96-101. http://www.ncbi.nlm.nih.gov/pubmed/?term=28976393
  12. Yildirim AB, Kilinc AY. [Dyslipidaemias in elderly patients]. Turk Kardiyoloji Dernegi arsivi : Turk Kardiyoloji Derneginin yayin organidir 2017; 45:25-28. http://www.ncbi.nlm.nih.gov/pubmed/?term=28976376
  13. Yang J, Zhu Q, Liu Q et al. Statin use and endometrial cancer risk: a meta-analysis. Oncotarget 2017; 8:62425-62434. http://www.ncbi.nlm.nih.gov/pubmed/?term=28977956
  14. van de Borne P. [Recent progresses in the treatment of dyslipidemia]. Revue medicale de Bruxelles 2017; 38:357-360. http://www.ncbi.nlm.nih.gov/pubmed/?term=28981240
  15. Stadler SL, Cook TJ. PCSK9 inhibitors and managing cost in the managed care setting. The American journal of managed care 2017; 23:S149-s155. http://www.ncbi.nlm.nih.gov/pubmed/?term=28978220
  16. Price JC, Tien PC. Editorial: Statins and Liver Disease: Is it Time to Recommend Statins to Prevent Liver Disease Progression? Am J Gastroenterol 2017; 112:1506-1507. http://www.ncbi.nlm.nih.gov/pubmed/?term=28978973
  17. Liu H, Xu X. Effect of simvastatin in patients with aneurysmal subarachnoid hemorrhage: A systematic review and meta-analysis. The American journal of emergency medicine 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28966073
  18. Hutchinson J, Marignol L. Clinical Potential of Statins in Prostate Cancer Radiation Therapy. Anticancer research 2017; 37:5363-5372. http://www.ncbi.nlm.nih.gov/pubmed/?term=28982844
  19. Hileman CO, McComsey GA. The Effect of Rosuvastatin on Vascular Disease Differs by Smoking Status in Treated HIV-Infection. AIDS research and human retroviruses 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28974102
  20. Defesche JC, Stefanutti C, Langslet G et al. Efficacy of alirocumab in 1191 patients with a wide spectrum of mutations in genes causative for familial hypercholesterolemia. J Clin Lipidol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28964736  
Miscellaneous publications
  1. Tang FC, Wang HY, Ma MM et al. Simvastatin attenuated rat thoracic aorta remodeling by decreasing ROCK2mediated CyPA secretion and CD147ERK1/2cyclin pathway. Mol Med Rep 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28983618
  2. Hassan SMS, Razzaque A, Ahmad Z et al. Does posttreatment thymoquinone reverse high-dose, atorvastatin-induced hepatic oxidative injury in rats? Canadian journal of physiology and pharmacology 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28968507
  3. Chiorescu S, Grad NO, Mironiuc IA, Andercou OA. Rosuvastatin administered intraperitoneally reduces the formation of postoperative adhesions in rats. Annali italiani di chirurgia 2017; 6. http://www.ncbi.nlm.nih.gov/pubmed/?term=28980533
  4. Ardeshna KP, Someshwar S, Rohatgi S, Jerajani HR. A Case of Psoriasis Vulgaris Aggravated with Atorvastatin, Aided by Concomitant Cyclosporine. Indian journal of dermatology 2017; 62:537-538. http://www.ncbi.nlm.nih.gov/pubmed/?term=28979024
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