European Journal of Clinical Pharmacology

, Volume 70, Issue 1, pp 99–108 | Cite as

Standard and intensive lipid-lowering therapy with statins for the primary prevention of vascular diseases: a population-based study

  • D. Macías Saint-GeronsEmail author
  • C. de la Fuente Honrubia
  • D. Montero Corominas
  • M. J. Gil
  • F. de Andrés-Trelles
  • F. Catalá-López
Pharmacoepidemiology and Prescription



To describe the clinical profile of the patients that initiate statin therapy for the primary prevention of vascular diseases and to investigate the extent to which clinicians use intensive vs. standard regimens.


A cross-sectional analysis of nationwide individual data regarding individuals ≥11 years with a first prescription of statin, recorded between 1 January 2007 and 31 December 2011. Subjects were defined as intensive therapy initiators if a statin dose superior to simvastatin 40 mg (or equivalent dose if different statin) was first prescribed. Multivariable logistic regression models were built for dependent summary variables to evaluate the strength of the association between them and the use of intensive therapy.


Overall, 69,737 patients receiving a first prescription of statin for the primary prevention of vascular diseases were identified. Predictors for intensive therapy initiation were male gender (adjusted OR: 1.28; 95%CI: 1.10–1.48), history of hypothyroidism (1.47; 1.17–1.85), current treatment of diabetes (1.18; 1.00–1.41), proteinuria (1.87; 1.12–3.12), age, and year of statin prescription. Modifiable risk factors associated with intensive therapy were elevated tryglicerides (1.63; 1.39–1.91), elevated LDL-C (1.96; 1.69–2.28), obesity (1.25; 1.07–1.47), smoking (1.32; 1.14–1.55), comedication with ezetimibe (3.76; 1.87–7.55), fibrates (1.96; 1.43–2.70) and calcium antagonists in women (1.42; 1.02–1.98).


The use of intensive therapy with statins in primary prevention was not very high in absolute terms, but is increasing considerably. The association between intensive therapy and previous hypothyroidism or its combination with fibrates may raise additional safety and tolerability concerns.


Pharmacoepidemiology Drug utilization study Hydroxymethylglutaryl-CoA reductase inhibitors Statin Intensive therapy Spain 



Authors would like to acknowledge the excellent collaboration of general practitioners taking part in BIFAP.



Conflict of Interest Statement

All authors have completed the Unified Competing Interest form at (available on request from the corresponding author) and declare: no support from any organisation for the submitted work and no financial relationships with any organisations that might have an interest in the submitted work in the previous 3 years and no other relationships or activities that could appear to have influenced the submitted work.

Contributions of Authors statement

All the authors have contributed substantially to the material and/or intellectual content, data analysis, if applicable, and the writing of the manuscript, sufficiently to accept public accountability for it.

Supplementary material

228_2013_1586_MOESM1_ESM.docx (29 kb)
ESM 1 (DOCX 28.7 KB)
228_2013_1586_MOESM2_ESM.doc (56 kb)
ESM 2 (DOC 55 kb)


  1. 1.
    Clark LT (2003) Treating dyslipidemia with statins: the risk-benefit profile. Am Heart J 145(3):387–396PubMedCrossRefGoogle Scholar
  2. 2.
    Scandinavian Simvastatin Group (1994) Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 344(8934):1383–1389Google Scholar
  3. 3.
    Naci H, Brugts JJ, Fleurence R, Tsoi B, Toor H, Ades A (2013) Comparative benefits of statins in the primary and secondary prevention of major coronary events and all-cause mortality: a network meta-analysis of placebo-controlled and active-comparator trials. Eur J Prev Cardiol 20(4):641–657PubMedCrossRefGoogle Scholar
  4. 4.
    Cholesterol Treatment Trialists’ (CTT), Mihaylova B, Emberson J, Blackwell L, Keech A, Simes J, Barnes EH, Voysey M, Gray A, Collins R, Baigent C (2012) The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 380(9841):581–590PubMedCrossRefGoogle Scholar
  5. 5.
    Taylor F, Huffman MD, Macedo AF, Moore TH, Burke M, Davey Smith G, Ward K, Ebrahim S (2013) Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev 31:1Google Scholar
  6. 6.
    Lazar LD, Pletcher MJ, Coxson PG, Bibbins-Domingo K, Goldman L (2011) Cost-effectiveness of statin therapy for primary prevention in a low-cost statin era. Circulation 124(2):146–153PubMedCrossRefGoogle Scholar
  7. 7.
    Catalá-López F, Sanfélix-Gimeno G, Ridao M, Peiró S (2013) When are statins cost-effective in cardiovascular prevention? A systematic review of sponsorship bias and conclusions in economic evaluations of statins. PLoS One 8(7):e69462. doi: 10.1371/journal.pone.0069462 PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Agencia Española de Medicamentos y Productos Sanitarios. Proyecto BIFAP Accessed July 2013
  9. 9.
    de Abajo FJ, Gil MJ, Bryant V, Timoner J, Oliva B, García-Rodríguez LA (2013) Upper gastrointestinal bleeding associated with NSAIDs, other drugs and interactions: a nested case–control study in a new general practice database. Eur J Clin Pharmacol 69(3):691–701PubMedCrossRefGoogle Scholar
  10. 10.
    Hernández-Díaz S, García Rodríguez LA (2006) Cardioprotective aspirin users and their excess risk of upper gastrointestinal complications. BMC Med 4:22PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    National Institute for Health and Clinical Excellence. Lipid modification. Cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease. NICE Clinical guideline 67. London: NICE, May 2008. Available from: Accessed July 2013
  12. 12.
    SIGN (Scottish Intercollegiate Guidelines Network). Risk estimation and the prevention of cardiovascular disease. Guideline No 97. ISBN 1899893997 Edinburgh: SIGN, 2007. Available on: Accessed July 2013
  13. 13.
    Maiques Galán A, Brotons Cuixart C, Villar Álvarez F, Navarro Pérez J, Lobos-Bejarano JM, Ortega Sánchez-Pinilla R, Martín Rioboó R, Banegas Banegas JR, Orozco-Beltrán D, Gil Guillén V (2012) Preventive cardiovascular recommendations. Aten Primaria 44(Supl 1):3–15CrossRefGoogle Scholar
  14. 14.
    National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) (2002) Third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 106(25):3143–3421Google Scholar
  15. 15.
    Fifth Joint Task Force of the European Society of Cardiology; European Association of Echocardiography; European Association of Percutaneous Cardiovascular Interventions; European Heart Rhythm Association; Heart Failure Association; European Association for Cardiovascular Prevention & Rehabilitation; European Atherosclerosis Society; International Society of Behavioural Medicine; European Stroke Organisation; European Society of Hypertension; European Association for the Study of Diabetes; European Society of General Practice/Family Medicine; International Diabetes Federation Europe; European Heart Network (2012) European guidelines on cardiovascular disease prevention in clinical practice (version 2012): the fifth joint task force of the European Society of Cardiology and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of nine societies and by invited experts). Eur J Prev Cardiol 19(4):585–667Google Scholar
  16. 16.
    Miller M, Stone NJ, Ballantyne C, Bittner V, Criqui MH, Ginsberg HN, Goldberg AC, Howard WJ, Jacobson MS, Kris-Etherton PM, Lennie TA, Levi M, Mazzone T, Pennathur S (2011) Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association 123(20):2292–2333Google Scholar
  17. 17.
    Cholesterol Treatment Trialists’ (CTT), Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, Peto R, Barnes EH, Keech A, Simes J, Collins R (2010) Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 376(9753):1670–1681PubMedCrossRefGoogle Scholar
  18. 18.
    Martin K, Bégaud B, Latry P, Miremont-Salamé G, Fourrier A, Moore N (2004) Differences between clinical trials and postmarketing use. Br J Clin Pharmacol 57(1):86–92PubMedCrossRefGoogle Scholar
  19. 19.
    Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, Joyal SV, Hill KA, Pfeffer MA, Skene AM (2004) Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 350(15):1495–1504PubMedCrossRefGoogle Scholar
  20. 20.
    Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH), Armitage J, Bowman L, Wallendszus K, Bulbulia R, Rahimi K, Haynes R, Parish S, Peto R, Collins R (2010) Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12,064 survivors of myocardial infarction: a double-blind randomised trial. Lancet 376(9753):1658–1669PubMedCrossRefGoogle Scholar
  21. 21.
    De Lemos JA, Blazing MA, Wiviott SD, Lewis EF, Fox KA, White HD, Rouleau JL, Pedersen TR, Gardner LH, Mukherjee R, Ramsey KE, Palmisano J, Bilheimer DW, Pfeffer MA, Califf RM, Braunwald E (2004) Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. JAMA 292(11):1307–1316PubMedCrossRefGoogle Scholar
  22. 22.
    Pedersen TR, Faergeman O, Kastelein JJ, Olsson AG, Tikkanen MJ, Holme I, Larsen ML, Bendiksen FS, Lindahl C, Szarek M, Tsai J (2005) High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. JAMA 294(19):2437–2445PubMedCrossRefGoogle Scholar
  23. 23.
    Amarenco P, Bogousslavsky J, Callahan A 3rd, Goldstein LB, Hennerici M, Rudolph AE, Sillesen H, Simunovic L, Szarek M, Welch KM, Zivin JA (2006) High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med 355:549–559PubMedCrossRefGoogle Scholar
  24. 24.
    Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ (2008) Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 359(21):2195–2207PubMedCrossRefGoogle Scholar
  25. 25.
    Crouse JR 3rd, Raichlen JS, Riley WA, Evans GW, Palmer MK, O’Leary DH, Grobbee DE, Bots ML, METEOR Study Group (2007) Effect of rosuvastatin on progression of carotid intima-media thickness in low-risk individuals with subclinical atherosclerosis: the METEOR TRIAL. JAMA 297(12):1344–1353PubMedCrossRefGoogle Scholar
  26. 26.
    Ito MK (2012) Dyslipidemia: management using optimal lipid-lowering therapy. Ann Pharmacother 46(10):1368–1381PubMedCrossRefGoogle Scholar
  27. 27.
    Ridker PM, Genest J, Boekholdt SM, Libby P, Gotto AM, Nordestgaard BG, Mora S, MacFadyen JG, Glynn RJ, Kastelein JJ (2010) HDL cholesterol and residual risk of first cardiovascular events after treatment with potent statin therapy: an analysis from the JUPITER trial. Lancet 376(9738):333–339PubMedCrossRefGoogle Scholar
  28. 28.
    Preiss D, Tikkanen MJ, Welsh P, Ford I, Lovato LC, Elam MB, LaRosa JC, DeMicco DA, Colhoun HM, Goldenberg I, Murphy MJ, MacDonald TM, Pedersen TR, Keech AC, Ridker PM, Kjekshus J, Sattar N, McMurray JJ (2012) Lipid-modifying therapies and risk of pancreatitis: a meta-analysis. JAMA 308(8):804–811PubMedCrossRefGoogle Scholar
  29. 29.
    Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ, Thomason MJ, Mackness MI, Charlton-Menys V, Fuller JH (2004) Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study. Lancet 364:685–896PubMedCrossRefGoogle Scholar
  30. 30.
    Duntas LH, Brenta G (2012) The effect of thyroid disorders on lipid levels and metabolism. Med Clin North Am 96(2):269–281PubMedCrossRefGoogle Scholar
  31. 31.
    Bruckert E, Hayem G, Dejager S, Yau C, Bégaud B (2005) Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients-the PRIMO study. Cardiovasc Drugs Ther 19(6):403–414PubMedCrossRefGoogle Scholar
  32. 32.
    Food and Drugs Administration (FDA). CRESTOR (AstraZeneca Pharmaceuticals LP) Label. Accessed July 2013
  33. 33.
    Dormuth CR, Hemmelgarn BR, Paterson JM, James MT, Teare GF, Raymond CB, Lafrance JP, Levy A, Garg AX, Ernst P (2013) Use of high potency statins and rates of admission for acute kidney injury: multicenter, retrospective observational analysis of administrative databases. BMJ 346:f880. doi: 10.1136/bmj.f880 PubMedCrossRefGoogle Scholar
  34. 34.
    Kostapanos MS, Milionis HJ, Elisaf MS (2010) Rosuvastatin-associated adverse effects and drug-drug interactions in the clinical setting of dyslipidemia. Am J Cardiovasc Drugs 10(1):11–28PubMedCrossRefGoogle Scholar
  35. 35.
    Pearson TA, Laurora I, Chu H, Kafonek S (2000) The lipid treatment assessment project (L-TAP): a multicenter survey to evaluate the percentages of dyslipidemic patients receiving lipid-lowering therapy and achieving low-density lipoprotein cholesterol goals. Arch Intern Med 160(4):459–467PubMedCrossRefGoogle Scholar
  36. 36.
    Desai DA, Zakaria S, Ouyang P (2012) Initiation of statin therapy: are there age limits? Curr Atheroscler Rep 14(1):17–25PubMedCrossRefGoogle Scholar
  37. 37.
    Savoie I, Kazanjian A (2002) Utilization of lipid-lowering drugs in men and women a reflection of the research evidence? J Clin Epidemiol 55(1):95–101PubMedCrossRefGoogle Scholar
  38. 38.
    Food and Drugs Administration (FDA). VYTORIN® (Merck&Co Inc) Label. Accessed July 2013
  39. 39.
    Amend KL, Landon J, Thyagarajan V, Niemcryk S, McAfee A (2011) Incidence of hospitalized rhabdomyolysis with statin and fibrate use in an insured US population. Ann Pharmacother 45(10):1230–1239PubMedCrossRefGoogle Scholar
  40. 40.
    Davidson MH, Armani A, McKenney JM, Jacobson TA (2007) Safety considerations with fibrate therapy. Am J Cardiol 99(6A):3C–18CPubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • D. Macías Saint-Gerons
    • 1
    Email author
  • C. de la Fuente Honrubia
    • 1
  • D. Montero Corominas
    • 1
  • M. J. Gil
    • 1
  • F. de Andrés-Trelles
    • 2
  • F. Catalá-López
    • 1
  1. 1.Division of Pharmacoepidemiology and PharmacovigilanceSpanish Agency for Medicines and Medical Devices (AEMPS)MadridSpain
  2. 2.Pharmacology Department, School of MedicineComplutense University of MadridMadridSpain

Personalised recommendations