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Impact of Statin Dosing Intensity on Transaminase and Creatine Kinase

  • Krista M. Dale
    Affiliations
    The University of Connecticut Schools of Pharmacy, Hartford, Conn.

    Storrs and Farmington; and the Divisions of Cardiology, Hartford, Conn.

    Drug Information, Hartford Hospital, Hartford, Conn.
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  • C. Michael White
    Affiliations
    The University of Connecticut Schools of Pharmacy, Hartford, Conn.

    Storrs and Farmington; and the Divisions of Cardiology, Hartford, Conn.

    Drug Information, Hartford Hospital, Hartford, Conn.
    Search for articles by this author
  • Nickole N. Henyan
    Affiliations
    The University of Connecticut Schools of Pharmacy, Hartford, Conn.

    Storrs and Farmington; and the Divisions of Cardiology, Hartford, Conn.

    Drug Information, Hartford Hospital, Hartford, Conn.
    Search for articles by this author
  • Jeffrey Kluger
    Affiliations
    The University of Connecticut Schools of Medicine, Hartford, Conn.

    Storrs and Farmington; and the Divisions of Cardiology, Hartford, Conn.
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  • Craig I. Coleman
    Correspondence
    Requests for reprints should be addressed to Craig I. Coleman, PharmD, Assistant Professor of Pharmacy, University of Connecticut, and Director, Pharmacoeconomics and Outcomes Studies Group, Hartford Hospital, Hartford, CT 06102-5037.
    Affiliations
    The University of Connecticut Schools of Pharmacy, Hartford, Conn.

    Storrs and Farmington; and the Divisions of Cardiology, Hartford, Conn.

    Drug Information, Hartford Hospital, Hartford, Conn.
    Search for articles by this author

      Abstract

      Purpose

      Higher intensity statin therapy reduces cardiovascular events more than lower intensity therapy, but the safety impact of higher intensity therapy is unknown. We performed a meta-analysis of randomized controlled trials comparing higher versus lower intensity therapy on liver and muscle safety.

      Methods

      A systematic literature search through January 2006 was conducted to identify randomized trials comparing higher versus lower intensity statin therapy meeting our criteria. Weighted averages were reported as relative risks (RRs) with 95% confidence intervals (random-effects model). Statistical heterogeneity scores were assessed with the Q statistic and L’Abbe plots. Publication bias was assessed with the Egger weighted regression and funnel plots.

      Results

      Higher intensity statin therapy increased the incidence of transaminase elevations (RR 3.10 [95% Confidence Interval [CI], 0.88-7.85]) versus lower intensity statin therapy. When studies of hydrophilic and lipophilic statins were evaluated separately, higher intensity hydrophilic statin therapy increased the risk for transaminase elevations (RR 3.54 [95% CI, 1.83-6.85]), but higher intensity lipophilic therapy did not (RR 1.58 [95% CI, 0.81-3.08]). The risk of creatine kinase (CK) elevations showed a trend toward an increase (RR 2.63 [95% CI, 0.88-7.85]) with higher intensity therapy. No occurrences of CK elevations occurred in studies evaluating hydrophilic statins, whereas lipophilic statins showed an increased risk with higher intensity therapy (RR 6.09 [95% CI, 1.36-27.35]).

      Conclusions

      More aggressive statin therapy increases the incidence of transaminase elevations in clinical trials versus lower intensity therapy. Increases in transaminases may be more problematic when hydrophilic statins are used aggressively, whereas CK elevations are more problematic with higher intensity lipophilic statin therapy.

      Keywords

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      References

        • Cannon C.P.
        • Braunwald E.
        • McCave Ch
        • et al.
        Intensive versus moderate lipid lowering with statin after acute coronary syndromes.
        N Engl J Med. 2004; 350: 1495-1504
        • LaRosa J.C.
        • Grundy S.M.
        • Waters D.D.
        • et al.
        Intensive lipid lowering with atorvastatin in patients with stable coronary disease.
        N Eng J Med. 2005; 352: 1425-1435
        • DerSimonian R.
        • Laird N.
        Meta-analysis in clinical trials.
        Controlled Clin Trials. 1986; 7: 177-188
        • Naylor A.F.
        Small sample considerations in combining 2×2 tables.
        Biometrics. 1967; 23: 349-356
        • Jadad A.R.
        • DPhil R.
        • Moore A.
        • et al.
        Assessing the quality of reports of randomized clinical trials: is blinding necessary?.
        Controlled Clin Trials. 1996; 17: 1-12
        • Mantel N.
        • Haenszel W.
        Statistical aspects of the analysis of data from retrospective studies of disease.
        J Natl Cancer Inst. 1957; 22: 719-748
        • deLemos J.A.
        • Blazing M.A.
        • Wiviott S.D.
        • et al.
        Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z Trial.
        JAMA. 2004; 292: 1307-1316
        • Taylor A.J.
        • Kent S.M.
        • Flaherty P.J.
        • et al.
        ARBITER: Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol: a randomized trial comparing the effects of atorvastatin and pravastatin on carotid intima medial thickness.
        Circulation. 2002; 206: 2055-2060
        • Nissen S.E.
        • Tuzcu E.M.
        • Schoenhagen P.
        • et al.
        Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial.
        JAMA. 2004; 291: 1071-1080
        • Raggi P.
        • Davidson M.
        • Callister T.Q.
        • et al.
        Aggressive versus moderate lipid-lowering therapy in hypercholesterolemic postmenopausal women: beyond endorsed lipid lowering with EBT scanning (BELLES).
        Circulation. 2005; 112: 563-571
        • Post-CABG: The Post Coronary Artery Bypass Graft Trial Investigators
        the effect of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous-vein coronary artery bypass grafts.
        N Engl J Med. 1997; 336: 153-162
        • Smilde T.J.
        • van Wissen S.
        • Wollersheim H.
        • et al.
        Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolaemia (ASAP): a prospective, randomized, double-blinded, trial.
        Lancet. 2001; 357: 577-581
        • Pedersen T.R.
        • Faergeman O.
        • Kastelein J.J.P.
        • et al.
        High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction, the IDEAL Study: a randomized controlled trial.
        JAMA. 2005; 294: 2437-2445
        • Tamai I.
        • Nezu J.
        • Uchino H.
        • et al.
        Molecular identification and characterization of novel members of the human organic anion transporter (OATP) family.
        Biochem Biophys Res Commun. 2000; 273: 251-260
        • McTavish D.
        • Sorkin E.M.
        Pravastatin: a review of its pharmacologic properties and therapeutic potential in hypercholesterolemia.
        Drugs. 1991; 42: 65-89
        • Negre-Aminou P.
        • Van Vliet A.K.
        • Van Erck M.
        • et al.
        Inhibition of proliferation of human smooth muscle cells by various HMG CoA reductase inhibitors: comparison with other human cell types.
        Biochemica et Biophysica Acta. 1997; 1345: 259-268
        • Newman C.
        • Szarek M.
        • Luo D.
        • et al.
        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: 61-67
        • White C.M.
        A review of pharmacologic and pharmacokinetic aspects of rosuvastatin.
        J Clin Pharmacol. 2002; 42: 963-970
        • White C.M.
        • Chow M.S.S.
        A review of HMG CoA reductase inhibitors.
        US Pharmacist. 1998; 23: H19-HS30
        • Staffa J.A.
        • Chang J.
        • Green L.
        Cerivastatin and reports of fatal rhabdomyolysis.
        N Engl J Med. 2002; 346: 539-540

      Linked Article

      • Impact of Statin Dosing Intensity on Transaminase and Creatine Kinase
        The American Journal of MedicineVol. 121Issue 2
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          Dale et al. in their meta-analysis1 concluded that more lipophilic statins (simvastatin and lovastatin) impose greater risk of muscle toxicity assessed by creatine kinase (CK) elevations than more hydrophilic statins (pravastatin and atorvastatin). In contrast, the more hydrophilic statins might be associated with a greater risk of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) abnormalities. However, some of these conclusions raise questions and require further discussion.
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