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Reinitiation of Statin Therapy After Discontinuation: A Meta-analysis

      To the Editor:
      The efficacy of statins in the prevention of cardiovascular disease has been well established.
      • Naci H.
      • Brugts J.J.
      • Fleurence R.
      • Tsoi B.
      • Toor H.
      • Ades A.E.
      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.
      However, many patients for whom statins are prescribed do not adhere to their medication regimen, and discontinuation from therapy is high, with over 30% of users discontinuing within 1 year.
      • Lemstra M.
      • Blackburn D.
      • Crawley A.
      • Fung R.
      Proportion and risk indicators of nonadherence to statin therapy: a meta-analysis.
      Statin discontinuation has been associated with poor clinical outcomes, with important economic implications.
      • Phan K.
      • Gomez Y.H.
      • Elbaz L.
      • Daskalopoulou S.S.
      Statin treatment non-adherence and discontinuation: clinical implications and potential solutions.
      Although patients discontinuing statin therapy may restart, to our knowledge no published systematic review has assessed reinitation rates. Understanding the patterns of reinitiation is important because the benefits of statin treatment accrue over time.

      Methods

      We conducted a systematic review to assess statin reinitiation rates by searching MEDLINE, EMBASE, CINAHL, and PsycINFO from inception to October 30, 2017, using terms including statins or HMG-CoA reductase inhibitors and discontinuation or persistence or reinitiation or resumption. The review followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines (Supplemental Table, available online at http://www.mayoclinicproceedings.org) and studies were appraised using a modified version of the National Institutes of Health Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies.
      National Institutes of Health, National Heart, Lung, and Blood Institute
      Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies.
      The proportion of statin discontinuers who reinitiated were pooled across studies through random effects meta-analysis. The between-study heterogeneity was quantified via the I2 statistic. The presence of publication bias was assessed by direct observations of funnel plots and quantified with Egger's regression test.
      • Higgins J.P.T.
      • Green S.
      Cochrane Handbook for Systematic Reviews of Interventions.
      The robustness of pooled estimates was determined through leave-one-out sensitivity assessments. Analyses were performed with OpenMeta[Analyst] software (Brown University School of Public Health).

      Results

      Following screening of 2763 articles, data from 8 studies conducted in Canada, the United States, Finland, Spain, and the United Kingdom involving 1,766,385 statin users were analyzed (Supplemental Figure, available online at http://www.mayoclinicproceedings.org). In these studies, statin discontinuation was defined by a refill gap ranging from 56 to 183 days and reinitiation as the dispensing of a statin prescription after a period of discontinuation. Across the studies, 42.0% (interquartile range, 37.2%-48.1%) of statin users discontinued their medication over a follow-up period ranging from 6 months to 12 years.
      Among the discontinuers, pooled proportions of 37.5% (95% CI, 34.7%-40.4%; I2=99.7%) and 50.6% (95% CI, 46.2%-55.0%; I2=99.9%) reinitiated within 6 months and 1 year, respectively, after discontinuation. The proportion of discontinuers who were likely to restart their statin treatment increased with duration of follow-up (Figure),
      • Brookhart M.A.
      • Patrick A.R.
      • Schneeweiss S.
      • et al.
      Physician follow-up and provider continuity are associated with long-term medication adherence: a study of the dynamics of statin use.
      • Vinogradova Y.
      • Coupland C.
      • Brindle P.
      • Hippisley-Cox J.
      Discontinuation and restarting in patients on statin treatment: prospective open cohort study using a primary care database.
      • Korhonen M.J.
      • Helin-Salmivaara A.
      • Huupponen R.
      Dynamics of long-term statin therapy.
      • Upmeier E.
      • Korhonen M.J.
      • Rikala M.
      • Helin-Salmivaara A.
      • Huupponen R.
      Older statin initiators in Finland - cardiovascular risk profiles and persistence of use.
      • Malo S.
      • Aguilar-Palacio I.
      • Feja C.
      • et al.
      Persistence with statins in primary prevention of cardiovascular disease: findings from a cohort of Spanish workers.
      • Booth J.
      • Colantonio L.
      • Chen S.
      • et al.
      Statin discontinuation, reinitiation, and persistence patterns among medicare beneficiaries after myocardial infarction.
      • Gibson T.
      • Fendrick A.
      • Gatwood J.
      • Chernew M.
      Gaps in treatment, treatment resumption, and cost sharing.
      • Caspard H.
      • Chan A.K.
      • Walker A.M.
      Compliance with a statin treatment in a usual-care setting: retrospective database analysis over 3 years after treatment initiation in health maintenance organization enrollees with dyslipidemia.
      reaching 78.0% (95% CI, 74.0%-82.0%; I2=99.9%) and 87.8% (95% CI, 85.9%-89.6%; I2=99.4%) at 5 and 10 years, respectively. The pooled estimates were unchanged by leave-one-out sensitivity analyses (plots not shown). Similarly, there was no evidence of publication bias as determined by Egger's regression test, which was insignificant at all follow-up periods (6 months, P=.91; 1 year, P=.44; 2 years, P=.60; 3 years, P=.45; 4 years, P=.83; 5 years, P=.99; and 10 years, P=.81).
      Figure thumbnail gr1
      FigurePooled proportions of statin discontinuers likely to restart at various follow-up periods. See (available online at http://www.mayoclinicproceedings.org) for references included in the analysis.
      The limitation of our meta-analysis is that the certainty in the pooled estimates (using the GRADE [Grading of Recommendations, Assessment, Development and Evaluations] approach) is very low due to substantial heterogeneity across the studies.

      Conclusion

      Our results demonstrate that a significant proportion of statin users restart following discontinuation. Although there is no universally accepted criteria for establishing statin discontinuation, the proportions restarting following a period of treatment cessation is encouraging. Nonetheless, interventions are needed to address the factors that promote discontinuation in order to avert cycles of treatment interruptions even among reinitiators. This focus is essential if the intended cardiovascular benefits of statin treatment are to be realized.

      Supplemental Online Material

      Supplemental material can be found online at: http://www.mayoclinicproceedings.org. Supplemental material attached to journal articles has not been edited, and the authors take responsibility for the accuracy of all data.

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      Linked Article

      • Correction
        Mayo Clinic ProceedingsVol. 93Issue 7
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          In the Letter to the Editor entitled, “Reinitiation of Statin Therapy After Discontinuation: A Meta-analysis” published in the May 2018 issue of Mayo Clinic Proceedings (Mayo Clin Proc. 2018;93(5):666-668), the publication dates for 2 of the studies listed in the Figure are incorrect. The year for Vinogradova et al7 should state 2016.
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