Skip to main content
SpringerLink
Log in

Safety Profile of Atorvastatin 80 mg: A Meta-Analysis of 17 Randomized Controlled Trials in 21,910 Participants

  • Systematic Review
  • Published:
Drug Safety Aims and scope Submit manuscript

Abstract

Introduction

Atorvastatin 80 mg/day has significant benefits for the primary and secondary prevention of cardiovascular and cerebrovascular disease. To our knowledge, no meta-analysis focusing on assessing the safety profile of atorvastatin 80 mg/day has been performed; therefore, our aim was to evaluate the tolerability and adverse event (AE) patterns of this drug/dose.

Methods

We conducted a search of the Cochrane Library, EMBASE and PubMed databases through to July 2015 for randomized controlled trials (RCTs). The safety endpoints included the incidence of discontinuations due to AEs, transaminase elevation, creatine kinase (CK) elevation, myalgia and rhabdomyolysis. We also conducted subgroup analyses according to the length of follow-up and clinical condition.

Results

Data from 17 RCTs involving 21,910 participants were included. Pooled analyses showed that atorvastatin 80 mg/day was less tolerable [risk ratio (RR) 1.29, 95 % confidence interval (CI) 1.17–1.42] and increased the risk of transaminase elevation (RR 4.59, 95 % CI 3.26–6.48) compared with controls. No significant difference was observed between the two groups in terms of the incidence of CK elevation (RR 1.38, 95 % CI 0.97–1.95), myalgia (RR 1.06, 95 % CI 0.93–1.20), and rhabdomyolysis (RR 0.67, 95 % CI 0.19–2.36).

Conclusions

Patients treated with atorvastatin 80 mg/day, specifically patients with coronary artery disease (CAD), have a higher risk of transaminase elevation, which is not seen if patient exposure is less than 16 weeks. Atorvastatin 80 mg/day is less well-tolerated compared with controls, especially in patients with CAD, but an overall favorable tolerability profile is found if patient exposure is less than 52 weeks.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Stancu C, Sima A. Statins: mechanism of action and effects. J Cell Mol Med. 2001;5(4):378–87.

    Article  CAS  PubMed  Google Scholar 

  2. Marzilli M. Pleiotropic effects of statins: evidence for benefits beyond LDL-cholesterol lowering. Am J Cardiovasc Drugs. 2010;10(Suppl 1):3–9.

    Article  CAS  PubMed  Google Scholar 

  3. Arca M, Gaspardone A. Atorvastatin efficacy in the primary and secondary prevention of cardiovascular events. Drugs. 2007;67(Suppl 1):29–42.

    Article  CAS  PubMed  Google Scholar 

  4. Ray KK, Cannon CP. Atorvastatin and cardiovascular protection: a review and comparison of recent clinical trials. Expert Opin Pharmacother. 2005;6(6):915–27.

    Article  CAS  PubMed  Google Scholar 

  5. LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;325(14):1425–35.

    Article  Google Scholar 

  6. Amarenco P, Bogousslavsky J, Callahan A 3rd, Goldstein LB, Hennerici M, Rudolph AE, et al. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006;355(6):549–59.

    Article  CAS  PubMed  Google Scholar 

  7. Cannon CP, Steinberg BA, Murphy SA, Mega JL, Braunwald E. Meta-analysis of cardiovascular outcomes trials comparing intensive versus moderate statin therapy. J Am Coll Cardiol. 2006;48(3):438–45.

    Article  CAS  PubMed  Google Scholar 

  8. Afilalo J, Majdan AA, Eisenberg MJ. Intensive statin therapy in acute coronary syndromes and stable coronary heart disease: a comparative meta-analysis of randomized controlled trials. Heart. 2007;93(8):914–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Newman CB, Palmer G, Silbershatz H, Szarek M. Safety of atorvastatin derived from analysis of 44 completed trials in 9,416 patients. Am J Cardiol. 2003;92(6):670–6.

    Article  CAS  PubMed  Google Scholar 

  10. van Wissen S, Smilde TJ, Trip MD, Stalenhoef AF, Kastelein JJ. Long-term safety and efficacy of high-dose atorvastatin treatment in patients with familial hypercholesterolemia. Am J Cardiol. 2005;95(2):264–6.

    Article  PubMed  Google Scholar 

  11. Bakker-Arkema RG, Nawrocki JW, Black DM. Safety profile of atorvastatin-treated patients with low LDL-cholesterol levels. Atherosclerosis. 2000;149(1):123–9.

    Article  CAS  PubMed  Google Scholar 

  12. Athyros VG, Tziomalos K, Karagiannis A, Mikhailidis DP. Atorvastatin: safety and tolerability. Expert Opin Drug Saf. 2010;9(4):667–74.

    Article  CAS  PubMed  Google Scholar 

  13. Newman C, Tsai J, Szarek M, Luo D, Gibson E. Comparative safety of atorvastatin 80 mg versus 10 mg derived from analysis of 49 completed trials in 14,236 patients. Am J Cardiol. 2006;97(1):61–7.

    Article  CAS  PubMed  Google Scholar 

  14. Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ. 2009;339:b2535.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Higgins JPT, Green S. Cochrane handbook for systematic reviews of interventions version 5.1.0 [updated March 2011]. The Cochrane Collaboration. 2011. http://www.cochrane-handbook.org. Accessed 2 Aug 2015.

  16. Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J, et al. GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables. J Clin Epidemiol. 2011;64(4):383–94.

    Article  PubMed  Google Scholar 

  17. Suleiman M, Koestler C, Lerman A, Lopez-Jimenez F, Herges R, Hodge D, et al. Atorvastatin for prevention of atrial fibrillation recurrence following pulmonary vein isolation: a double-blind, placebo-controlled, randomized trial. Heart Rhythm. 2012;9(2):172–8.

    Article  PubMed  Google Scholar 

  18. Bone HG, Kiel DP, Lindsay RS, Lewiecki EM, Bolognese MA, Leary ET, et al. Effects of atorvastatin on bone in postmenopausal women with dyslipidemia: a double-blind, placebo-controlled, dose-ranging trial. J Clin Endocrinol Metab. 2007;92(12):4671–7.

    Article  CAS  PubMed  Google Scholar 

  19. Bonnet J, McPherson R, Tedgui A, Simoneau D, Nozza A, Martineau P, et al. Comparative effects of l0-mg versus 80-mg atorvastatin on high-sensitivity C-reactive protein in patients with stable coronary artery disease: results of the CAP (Comparative Atorvastatin Pleiotropic Effects) study. Clin Ther. 2008;30(12):2298–313.

    Article  CAS  PubMed  Google Scholar 

  20. Colivicchi F, Tubaro M, Mocini D, Genovesi Ebert A, Strano S, Melina G, et al. Full-dose atorvastatin versus conventional medical therapy after non-ST-elevation acute myocardial infarction in patients with advanced non-revascularisable coronary artery disease. Curr Med Res Opin. 2010;26(6):1277–84.

    Article  CAS  PubMed  Google Scholar 

  21. Tawakol A, Fayad ZA, Mogg R, Alon A, Klimas MT, Dansky H, et al. Intensification of statin therapy results in a rapid reduction in atherosclerotic inflammation. J Am Coll Cardiol. 2013;62(10):909–17.

    Article  CAS  PubMed  Google Scholar 

  22. Kaul U, Varma J, Kahali D, Hiremath MS, Dani S, Dalal J, et al. Post-marketing study of clinical experience of atorvastatin 80 mg vs 40 mg in Indian patients with acute coronary syndrome- a randomized, multi-centre study (CURE-ACS). J Assoc Physicians India. 2013;61(2):97–101.

    PubMed  Google Scholar 

  23. Blom DJ, Hala T, Bolognese M, Lillestol MJ, Toth PD, Burgess L, et al. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med. 2014;370(19):1809–19.

    Article  CAS  PubMed  Google Scholar 

  24. Jones PH, Bays HE, Davidson MH, Kelly MT, Buttler SM, Setze CM, et al. Evaluation of a new formulation of fenofibric acid, ABT-335, co-administered with statins: study design and rationale of a phase III clinical programme. Clin Drug Investig. 2008;28(10):625–34.

    Article  CAS  PubMed  Google Scholar 

  25. Karalis DG, Ross AM, Vacari RM, Zarren H, Scott R. Comparison of efficacy and safety of atorvastatin and simvastatin in patients with dyslipidemia with and without coronary heart disease. Am J Cardiol. 2002;89(6):667–71.

    Article  CAS  PubMed  Google Scholar 

  26. Schwartz GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, Waters D, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA. 2001;285(13):1711–8.

    Article  CAS  PubMed  Google Scholar 

  27. Jones PH, McKenney JM, Karalis DG, Downey J. Comparison of the efficacy and safety of atorvastatin initiated at different starting doses in patients with dyslipidemia. Am Heart J. 2005;149(1):e1.

    Article  PubMed  Google Scholar 

  28. Schmermund A, Achenbach S, Budde T, Buziashvili Y, Förster A, Friedrich G, et al. Effect of intensive versus standard lipid-lowering treatment with atorvastatin on the progression of calcified coronary atherosclerosis over 12 months: a multicenter, randomized, double-blind trial. Circulation. 2006;113(3):427–37.

    Article  CAS  PubMed  Google Scholar 

  29. Parker BA, Capizzi JA, Grimaldi AS, Clarkson PM, Cole SM, Keadle J, et al. Effect of statins on skeletal muscle function. Circulation. 2013;127(1):96–103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Yu CM, Zhang Q, Lam L, Lin H, Kong SL, Chan W, et al. Comparison of intensive and low-dose atorvastatin therapy in the reduction of carotid intimal-medial thickness in patients with coronary heart disease. Heart. 2007;93(8):933–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Zhao Z, Geng J, Ge ZM, Wang W, Zhang Y, Kang WQ. Efficacy and safety of atorvastatin during early hospitalization in elderly patients with unstable angina. Clin Exp Pharmacol Physiol. 2009;36(5–6):554–8.

    Article  CAS  PubMed  Google Scholar 

  32. Koren MJ, Hunninghake DB. ALLIANCE Investigators. Clinical outcomes in managed-care patients with coronary hear disease treated aggressively in lipid-lowering disease management clinics: the alliance study. J Am Coll Cardiol. 2004;44(9):1772–9.

    PubMed  Google Scholar 

  33. Nissen SE, Tuzcu EM, Schoenhagen P, Brown BG, Ganz P, Vogel RA, et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA. 2004;291(9):1071–80.

    Article  CAS  PubMed  Google Scholar 

  34. Armitage J. The safety of statins in clinical practice. Lancet. 2007;370(9601):1781–90.

    Article  CAS  PubMed  Google Scholar 

  35. Water DD. Safety of high-dose atorvastatin therapy. Am J Cardiol. 2005;96(5A):69F–75F.

    Article  Google Scholar 

  36. Alberton M, Wu P, Druyts E, Briel M, Mills EJ. Adverse events associated with individual statin treatments for cardiovascular disease: an indirect comparison meta-analysis. QJM. 2012;105(2):145–57.

    Article  CAS  PubMed  Google Scholar 

  37. Naci H, Brugts J, Ades T. Comparative tolerability and harms of individual statins: a study-level network meta-analysis of 246955 participants from 135 randomized, controlled trials. Circ Cardiovasc Qual Outcomes. 2013;6(4):390–9.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

The authors gratefully acknowledge Dr. David Jack for his assistance with language editing.

Author information

Authors and Affiliations

  1. Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, China

    Haixia Li, Shuo Zhang, Sihao Sun, Ruifei Li, Meijuan Zou & Gang Cheng

  2. Department of Cardiology, General Hospital of Shenyang Military Area, Shenhe District, Shenyang, China

    Cailian Wang

Authors
  1. Haixia Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cailian Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shuo Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sihao Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ruifei Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Meijuan Zou
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Gang Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gang Cheng.

Ethics declarations

Funding

No sources of funding were used to assist in the preparation of this study.

Conflicts of interest

Haixia Li, Cailian Wang, Suo Zhang, Sihao Sun, Ruifei Li, Meijuan Zou and Gang Cheng have no conflicts of interest that are directly relevant to the content of this study.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 Fig. 1 Risk of bias summary of each included study (PDF 189 kb)

40264_2016_394_MOESM2_ESM.pdf

Supplementary material 2 Fig. 2 Funnel plot assessing publication bias in discontinuations because of adverse events. SE standard error (PDF 127 kb)

40264_2016_394_MOESM3_ESM.pdf

Supplementary material 3 Fig. 3 Forest plots of subgroup analyses for discontinuations because of adverse events: (a) long-term (≥52 weeks) and short-term (<52 weeks) subgroups; (b) dyslipidemia and coronary artery disease subgroups (PDF 232 kb)

40264_2016_394_MOESM4_ESM.pdf

Supplementary material 4 Fig. 4 Funnel plot assessing publication bias in ALT/AST elevation. SE standard error (PDF 126 kb)

40264_2016_394_MOESM5_ESM.pdf

Supplementary material 5 Fig. 5 Forest plots of subgroup analyses for ALT/AST elevation: (a) long-term (≥16 weeks) and short-term (<16 weeks) subgroups; (b) dyslipidemia and coronary artery disease subgroups (PDF 250 kb)

Supplementary material 6 Fig. 6 Funnel plot assessing publication bias in CK elevation. SE standard error (PDF 126 kb)

Supplementary material 7 Fig. 7 Funnel plot assessing publication bias in myalgia. SE standard error (PDF 126 kb)

Supplementary material 8 (PDF 88 kb)

Supplementary material 9 (PDF 88 kb)

Supplementary material 10 (PDF 87 kb)

Supplementary material 11 (PDF 191 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, H., Wang, C., Zhang, S. et al. Safety Profile of Atorvastatin 80 mg: A Meta-Analysis of 17 Randomized Controlled Trials in 21,910 Participants. Drug Saf 39, 409–419 (2016). https://doi.org/10.1007/s40264-016-0394-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40264-016-0394-0

Keywords

Search

Navigation