Protocol for a Systematic Review and Meta-Analysis of Randomized Controlled Trials

Appendix 1.Protocol

Do Statins Impair Cognition?

Protocol for a Systematic Review and Meta-Analysis of Randomized Controlled Trials

Brian R. Ott, MD, Lori A. Daiello, PharmD, ScM, Issa J. Dahabreh, MD, MS

Beth A. Springate, PhD, Kimberly Bixby, BS,ManjariMurali, PhD,Thomas A. Trikalinos, MD

Background and Significance

The basis for disagreement between reports of clinically significant adverse effects of statins on cognition and the accumulated evidence from RCTs remains unclear. To address this conundrum, we will perform a systematic review and meta-analysis (when possible) of cognitive test results and adverse event reports from randomized controlled trials (RCTs) of statin treatment in two major groups of subjects: 1) cognitively normal older adults, and 2) persons with dementia or other forms of cognitive impairment.

Review Question(s)

1)To determine the effects of statins on cognitive function in two groups: adults with normal cognition, and those with dementia or other type of cognitive impairment.

2)To determine whether blood-brain barrier penetrability differentiates among statins more likely to be associated with adverse cognitive effects

Searches

The literature search strategy will include four components: 1) a search for statin RCTs identified in three previous Cochrane reviews that examined cognitive outcomes for the prevention 23 and treatment of dementia,24 and another that examined statins for the primary prevention of cardiovascular outcomes.25 This strategy will capture statin RCTs published through 2008; 2) a search of the Cochrane Central registry of trials and the MEDLINE, EMBASE databases for RCTs of statins with neurocognitive outcomes through 2008 to identify trials that those Cochrane reviews may have excluded; 3) an additional search of these databases to identify statin RCTs, irrespective of outcomes, between 2008 and December 2012; and 4) and a search for additional statin RCTs from a network meta-analysis of statins and adverse effects.26

Types of studies to be included

All RCTs of statins approved for use in the U.S. or Europe (simvastatin, rosuvastatin, atorvastatin, fluvastatin, pravastatin, lovastatin, mevastatin, cerivastatin, pitavastatin) with or without other lipid lowering agents. Trials of statins performed in humans, published in English, mean number of participants per arm >10, and with any duration of follow-up.

Condition or domain being studied

Cognitive impairment, regardless of diagnosis, that is measured by validated rating scales.

Participants/ population

No studies will be excluded based on patient characteristics.

Intervention(s), exposure(s)

RCTs comparing statin therapy with or without other lipid lowering agents, versus no statins.

Comparator(s)/ control

Placebo

Outcome(s)

Primary outcome
Measures of overall cognitive functioning from global cognitive scales, neuropsychological test performance in individual cognitive domains (executive function, attention, processing speed, memory, working memory), or global measures constructed by combining cognitive domain scores. Dichotomous classifications of cognitive impairment (e.g., dementia vs. no dementia).

Secondary outcome
Incidence of cognitive-related, treatment emergent adverse events (e.g. memory loss, forgetfulness, amnesia, memory impairment, and confusion), by statin lipophilicity.

Data extraction, (selection and coding)

A pilot round of the same 300 abstracts using Abstrackr software will be conducted with all authors to ensure accuracy during the screening stage.27 Papers that are selected in the abstract screening phase will be retrieved and examined in full text for eligibility. Two reviewers will read the studies to determine the final study selection. Disagreements will be evaluated by one of the principal investigators (BO or LD) and discrepancies resolved with the involvement of a third reviewer (TT or ID) when necessary.

The data will then be extracted by one author, and verified by another. To ensure accuracy, one reviewer will record the information using the data abstraction form, and another will independently verify the results. The analysis dataset will be made available via the Systematic Review Data Repository (SRDR).25

Data to extract
Participant characteristics, study characteristics including objectives, year of publication, sample size, setting, country, funding mechanism, duration of follow up, randomization method, reporting of dropouts, intervention and comparator details, and cognitive outcomes and harms. For categorical outcomes we will extract the number experiencing the outcome in each arm. For continuous outcomes, test scores to calculate the mean differences at end of follow-up will be extracted. Differences in net changes (i.e., final minus baseline values between groups) will be extracted only when mean differences of final values are unavailable.28

Risk of bias (quality) assessment

The presence or absence of bias will be assessed with methodological items that correspond to those included in the Cochrane Risk of Bias tool29 (adequacy of random sequence generation, allocation concealment, blinding to treatment assignment, completeness of follow-up data (defined as loss to follow-up and treatment discontinuation rates lower than 20%), and lack of differential loss to follow-up or treatment discontinuation (defined as Fisher’s exact p-value >0.05 or difference in absolute rates <5%, across study groups)) and will be entered into SRDR. Two independent reviewers will rate risk of bias as high, low, or unclear for each item and discrepancies will be resolved by consensus. Meta-regression weighted least squares analyses will be performed for risk of bias item when items are variable across studies, and 6 or more studies are available for the analysis.

Strategy for data synthesis

Results of the systematic review will be described narratively.

Meta-analyses will be performed with random effects models fit with weighted least-squares methods when information from two or more RCTs is available. Separate meta-analyses will be performed for RCTs in cognitively normal subjects, and in patients with dementia or other types of cognitive impairment. Continuous outcomes reported on the same scale (e.g., ADAS-Cog,30 MMSE31) will be considered as weighted mean differences at study endpoint. For continuous outcomes reported on different scales will be summarized as standardized mean differences (SMDs), using the Hedges g metric and the robust variance estimator.34,32. P-values and 95% confidence intervals will be calculated for effect estimates. Between-study heterogeneity will be assessed using the estimated between-study standard deviation (e.g., τ, the square root of the between-study variance).

Subgroup analyses
Random effects meta-regression with weighted least squares will be utilized to investigate the contribution of degree of blood brain barrier penetrability to between-study differences for cognitive effects, categorizing statins according to higher vs. lower propensity to cross the blood-brain barrier.35

Summary

By performing the systematic review and applying meta-analytic methods(where appropriate) to analyze both neuropsychological test change scores and discrete adverse event reports, we hope to advance the understanding of the association between statins and adverse cognitive effects that warrant discontinuation of the medication. This is a question with major public health implications due to 1) the increasingly high prevalence of statin use in the U.S. and the world, and 2) the known health benefits of statin therapy in the primary and secondary prevention of cardiovascular and cerebrovascular death and morbidity.

Appendix 2. Systematic review literature search strategy

A. Strategy for randomized clinical trials in non-dementia patients

CENTRAL on The Cochrane Library

1. MeSH descriptor Hydroxymethylglutaryl-CoAReductase Inhibitors explode all trees

2.statin or statins

3.atorvastatin

4.cerivastatin

5.fluvastatin

6.lovastatin

7.pravastatin

8.simvastatin

9.pitavastatin

10.lipitor

11.baycol

12.lescol

13.mevacor

14.altocor

15.pravachol

16.lipostat

17.zocor

18.rosuvastatin

19.Livalo

20. (hydroxymethylglutaryl next coenzyme next reductase next inhibitor)

21. (#1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9)

22. (#10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19)

23. (#21 or #22)

MEDLINE on Ovid

1.expHydroxymethylglutaryl-CoAReductase Inhibitors/

2. (statin or statins).tw.

3.atorvastatin.tw.

4.cerivastatin.tw.

5.fluvastatin.tw.

6.lovastatin.tw.

7.pravastatin.tw.

8.simvastatin.tw.

9.pitavastatin.tw.

10.lipitor.tw.

11.baycol.tw.

12.lescol.tw.

13.mevacor.tw.

14.altocor.tw.

15.pravachol.tw.

16.lipostat.tw.

17.zocor.tw.

18.mevinolin.tw.

19.compactin.tw.

20.fluindostatin.tw.

21.rosuvastatin.tw.

22.livalo.tw.

23. or/1-22

24.exp Cardiovascular Diseases/

25.cardiovascular.tw.

26.heart disease$.tw.

27.coronary disease$.tw.

28.angina.tw.

29.heart failure.tw.

30.cardiac failure.tw.

31.expHyperlipidemia/

32.hyperlipid$.tw.

33.hypercholesterol$.tw.

34.exp Cholesterol/

35.cholesterol$.tw.

36.randomized controlled trial.pt.

37. controlled clinical trial.pt.

38. Randomized controlled trials/

39.random allocation.sh.

40.double blind method.sh.

41. single-blind method.sh.

42. or/36-41

43.exp animal/ not human/

44. 42 not 43

45.clinical trial.pt.

46.exp Clinical trials/

47. (clin$ adj25 trial$).ti,ab.

48. ((singl$ or doubl$ or trebl$ or tripl$) adj (blind$ or mask$)).ti,ab.

49.placebos.sh.

50.placebo$.ti,ab.

51.random$.ti,ab.

52.research design.sh.

53. or/45-52

54. 53 not 43

55. 44 or 54

56. or/24-35

57. 23 and 56 and 55

MEDLINE on Ovid (randomized trial terms omitted)

1.expHydroxymethylglutaryl-CoAReductase Inhibitors/

2. (statin or statins).tw.

3.atorvastatin.tw.

4.cerivastatin.tw.

5.fluvastatin.tw.

6.lovastatin.tw.

7.pravastatin.tw.

8.simvastatin.tw.

9.pitavastatin.tw.

10.lipitor.tw.

11.baycol.tw.

12.lescol.tw.

13.mevacor.tw.

14.altocor.tw.

15.pravachol.tw.

16.lipostat.tw.

17.zocor.tw.

18.mevinolin.tw.

19.compactin.tw.

20.fluindostatin.tw.

21.rosuvastatin.tw.

22.livalo.tw.

23. or/1-22

24.exp Cardiovascular Diseases/

25.cardiovascular.tw.

26.heart disease$.tw.

27.coronary disease$.tw.

28.angina.tw.

29.heart failure.tw.

30.cardiac failure.tw.

31.expHyperlipidemia/

32.hyperlipid$.tw.

33.hypercholesterol$.tw.

34.exp Cholesterol/

35.cholesterol$.tw.

36.randomized controlled trial.pt.

37. controlled clinical trial.pt.

38. Randomized controlled trials/

39.random allocation.sh.

40.double blind method.sh.

41. single-blind method.sh.

42. or/24-35

43.exp animal/ not human/

44. 42 not 43

45. 23 and 44

EMBASE on Ovid

1.expHydroxymethylglutaryl Coenzyme Reductase Inhibitor/

2. (statin or statins).tw.

3.atorvastatin.tw.

4.cerivastatin.tw.

5.fluvastatin.tw.

6.lovastatin.tw.

7.pravastatin.tw.

8.simvastatin.tw.

9.pitavastatin.tw.

10.lipitor.tw.

11.baycol.tw.

12.lescol.tw.

13.mevacor.tw.

14.altocor.tw.

15.pravachol.tw.

16.lipostat.tw.

17.zocor.tw.

18.mevinolin.tw.

19.compactin.tw.

20.fluindostatin.tw.

21.rosuvastatin.tw.

22.livalo.tw.

23. or/1-22

24.exp Cardiovascular Disease/

25.cardiovascular.tw.

26.heart disease$.tw.

27.coronary disease$.tw.

28.angina.tw.

29.heart failure.tw.

30.cardiac failure.tw.

31.expHyperlipidemia/

32.hyperlipid$.tw.

33.hypercholesterol$.tw.

34.exp Cholesterol/

35.cholesterol$.tw.

36.exp lipid blood level/

37. or/24-36

38. 23 and 37

39.random$.ti,ab.

40.factorial$.ti,ab.

41. (crossover$ or cross over$ or cross-over$).ti,ab.

42.placebo$.ti,ab.

43. (double$ adj blind$).ti,ab.

44. (singl$ adj blind$).ti,ab.

45.assign$.ti,ab.

46.allocat$.ti,ab.

47.volunteer$.ti,ab.

48. Crossover Procedure/

49. Double Blind Procedure/

50. Randomized Controlled Trial/

51. Single Blind Procedure/

52. or/39-51

53.exp animal/

54.nonhuman/

55.exp animal experiment/

56. or/53-55

57.exp human/

58. 56 not 57

59. 52 not 58

60. 38 and 59

EMBASE on Ovid (randomized trial terms omitted)

1.expHydroxymethylglutaryl Coenzyme Reductase Inhibitor/

2. (statin or statins).tw.

3.atorvastatin.tw.

4.cerivastatin.tw.

5.fluvastatin.tw.

6.lovastatin.tw.

7.pravastatin.tw.

8.simvastatin.tw.

9.pitavastatin.tw.

10.lipitor.tw.

11.baycol.tw.

12.lescol.tw.

13.mevacor.tw.

14.altocor.tw.

15.pravachol.tw.

16.lipostat.tw.

17.zocor.tw.

18.mevinolin.tw.

19.compactin.tw.

20.fluindostatin.tw.

21.rosuvastatin.tw.

22.livalo.tw.

23. or/1-22

24.exp Cardiovascular Disease/

25.cardiovascular.tw.

26.heart disease$.tw.

27.coronary disease$.tw.

28.angina.tw.

29.heart failure.tw.

30.cardiac failure.tw.

31.expHyperlipidemia/

32.hyperlipid$.tw.

33.hypercholesterol$.tw.

34.exp Cholesterol/

35.cholesterol$.tw.

36.exp lipid blood level/

37. or/24-36

38. 23 and 37

39.exp animal/

40.nonhuman/

41.exp animal experiment/

42. or/39-41

43.exp human/

44. 42 not 43

45. 38 and 44

B. Strategy for randomized clinical trials in dementia patients

The Cochrane Library

1. statin*.tiabkw.

2. hydroxymethylglutaryl-CoAReductase Inhibitors/ (all subheadings)

3. 1 OR 2

4. Alzheimer-disease/ all subheadings

5.exp dementia-vascular/ all subheadings

6.creutzfeldt-jakob-syndrome/ all subheadings

7.kluver-bucy-syndrome/ all subheadings

8.lewy-body-disease/ all subheadings

9.pick-disease-of-the-brain/ all subheadings

10.Huntington-disease/ all subheadings

11.delirium/ all subheadings

12.wernicke-encephalopathy/ all subheadings

13.mild-cognitive-impairment/all subheadings

14.(dement$ OR Alzheimer$).tiab.

15.(lewy$ AND bod$).tiab.

16.((cognit$ OR memor$ OR mental) and (decline$ OR impair$ OR los$ OR deteriorate$)).tiab.

17.(chronic AND cerebrovascular).tiab.

18.((organic brain syndrome) OR (organic brain disease)).tiab.

19.((cerebr$ AND deteriorate$) OR (cerebr$ AND insufficien$)).tiab.

20.((pick$ and disease) or (creutzfeldt or JCD or CJD) or huntington$ or binswanger$ or korsako$).tiab.

21. 4 OR 5 OR 6 OR 7 OR 8 OR 9 OR 10 OR 11 OR 12 OR 13 OR 14 OR 15 OR 16 OR 17 OR 18 OR 19 OR 20

22. 21 AND 4

23. limit 22 to (randomized controlled trial).pt.

NOTE: Run with and without item 23

Medline (Ovid SP) – Randomized trials

1.(statin$ OR lipophilic OR hydrophilic).mp.

2.(lovastatin OR simvastatin OR cervistatin OR atorvastatin OR rosuvastatin OR pravastatin OR fluvastatin OR pitavastatin).mp.

3.Hydroxymethylglutaryl-CoAReductase Inhibitors/ all subheadings

4.Alzheimer-disease/ all subheadings

5.exp dementia-vascular/ all subheadings

6.creutzfeldt-jakob-syndrome/ all subheadings

7.kluver-bucy-syndrome/ all subheadings

8.lewy-body-disease/ all subheadings

9.pick-disease-of-the-brain/ all subheadings

10.Huntington-disease/ all subheadings

11.delirium/ all subheading

12.wernicke-encephalopathy/ all subheadings

13.mild-cognitive-impairment/ all subheadings

14.(dement$ OR Alzheimer$).mp.

15.(lewy$ AND bod$).mp.

16.((cognit$ OR memor$ OR mental) and (decline$ OR impair$ OR los$ OR deteriorate$)).mp.

17.(chronic AND cerebrovascular).mp.

18.((organic brain syndrome) OR (organic brain disease)).mp.

19.((cerebr$ AND deteriorate$) OR (cerebr$ AND insufficien$)).mp.

20.((pick$ and disease) or (creutzfeldt or JCD or CJD) or huntington$ or binswanger$ or korsako$).mp.

21.1 OR 2 OR 3

22.4 OR 5 OR 6 OR 7 OR 8 OR 9 OR 10 OR 11 OR 12 OR 13 OR 14 OR 15 OR 16 OR 17 OR 18 OR 19 OR 20

23.21 AND 22

24.randomized controlled trial.pt.

25.controlled clinical trial.pt.

26.randomized.ab.

27.placebo.ab.

28.drugtherapy.fs.

29.randomly.ab.

30.trial.ab.

31.groups.ab.

32.24 OR 25 OR 26 OR 27 OR 28 OR 29 OR 30 OR 31

33.humans.sh.

34.32 AND 33

35.23 AND 34

Medline (Ovid SP) – Without Randomized trials

1.(statin$ OR lipophilic OR hydrophilic).mp.

2.(lovastatin OR simvastatin OR cervistatin OR atorvastatin OR rosuvastatin OR pravastatin OR fluvastatin OR pitavastatin).mp.

3.Hydroxymethylglutaryl-CoAReductase Inhibitors/ all subheadings

4.Alzheimer-disease/ all subheadings

5.exp dementia-vascular/ all subheadings

6.creutzfeldt-jakob-syndrome/ all subheadings

7.kluver-bucy-syndrome/ all subheadings

8.lewy-body-disease/ all subheadings

9.pick-disease-of-the-brain/ all subheadings

10.Huntington-disease/ all subheadings

11.delirium/ all subheading

12.wernicke-encephalopathy/ all subheadings

13.mild-cognitive-impairment/ all subheadings

14.(dement$ OR Alzheimer$).mp.

15.(lewy$ AND bod$).mp.

16.((cognit$ OR memor$ OR mental) and (decline$ OR impair$ OR los$ OR deteriorate$)).mp.

17.(chronic AND cerebrovascular).mp.

18.((organic brain syndrome) OR (organic brain disease)).mp.

19.((cerebr$ AND deteriorate$) OR (cerebr$ AND insufficien$)).mp.

20.((pick$ and disease) or (creutzfeldt or JCD or CJD) or huntington$ or binswanger$ or korsako$).mp.

21.1 OR 2 OR 3

22.4 OR 5 OR 6 OR 7 OR 8 OR 9 OR 10 OR 11 OR 12 OR 13 OR 14 OR 15 OR 16 OR 17 OR 18 OR 19 OR 20

23.21 AND 22

24.humans.sh.

25.23 AND 24

Embase (Ovid SP) – Randomized trials

1.(statin$ OR lipophilic OR hydrophilic).mp.

2.(lovastatin OR simvastatin OR cervistatin OR atorvastatin OR rosuvastatin OR pravastatin OR fluvastatin OR pitavastatin).mp.

3.Hydroxymethylglutaryl-CoAReductase Inhibitors/ all subheadings

4.Alzheimer-disease/ all subheadings

5.exp dementia-vascular/ all subheadings

6.creutzfeldt-jakob-syndrome/ all subheadings

7.kluver-bucy-syndrome/ all subheadings

8.lewy-body/ all subheadings

9.pick-presenile-dementia/ all subheadings

10.Huntington-chorea/ all subheadings

11.delirium/ all subheading

12.wernicke-encephalopathy/ all subheadings

13.mild-cognitive-impairment/ all subheadings

14.(dement$ OR Alzheimer$).mp.

15.(lewy$ AND bod$).mp.

16.((cognit$ OR memor$ OR mental) and (decline$ OR impair$ OR los$ OR deteriorate$)).mp.

17.(chronic AND cerebrovascular).mp.

18.((organic brain syndrome) OR (organic brain disease)).mp.

19.((cerebr$ AND deteriorate$) OR (cerebr$ AND insufficien$)).mp.

20.((pick$ and disease) or (creutzfeldt or JCD or CJD) or huntington$ or binswanger$ or korsako$).mp.

21.1 OR 2 OR 3

22.4 OR 5 OR 6 OR 7 OR 8 OR 9 OR 10 OR 11 OR 12 OR 13 OR 14 OR 15 OR 16 OR 17 OR 18 OR 19 OR 20

23.21 AND 22

24.randomized controlled trial.pt.

25.controlled clinical trial.pt.

26.randomized.ab.

27.placebo.ab.

28.drugtherapy.fs.

29.randomly.ab.

30.trial.ab.

31.groups.ab.

32.24 OR 25 OR 26 OR 27 OR 28 OR 29 OR 30 OR 31

33.humans.sh.

34.32 AND 33

35.23 AND 33

Embase (Ovid SP) – Without Randomized trials

1.(statin$ OR lipophilic OR hydrophilic).mp.

2.(lovastatin OR simvastatin OR cervistatin OR atorvastatin OR rosuvastatin OR pravastatin OR fluvastatin OR pitavastatin).mp.

3.Hydroxymethylglutaryl-CoAReductase Inhibitors/ all subheadings

4.Alzheimer-disease/ all subheadings

5.exp dementia-vascular/ all subheadings

6.creutzfeldt-jakob-syndrome/ all subheadings

7.kluver-bucy-syndrome/ all subheadings

8.lewy-body/ all subheadings

9.pick-presenile-dementia/ all subheadings

10.Huntington-chorea/ all subheadings

11.delirium/ all subheading

12.wernicke-encephalopathy/ all subheadings

13.mild-cognitive-impairment/ all subheadings

14.(dement$ OR Alzheimer$).mp.

15.(lewy$ AND bod$).mp.

16.((cognit$ OR memor$ OR mental) and (decline$ OR impair$ OR los$ OR deteriorate$)).mp.

17.(chronic AND cerebrovascular).mp.

18.((organic brain syndrome) OR (organic brain disease)).mp.

19.((cerebr$ AND deteriorate$) OR (cerebr$ AND insufficien$)).mp.

20.((pick$ and disease) or (creutzfeldt or JCD or CJD) or huntington$ or binswanger$ or korsako$).mp.

21.1 OR 2 OR 3

22.4 OR 5 OR 6 OR 7 OR 8 OR 9 OR 10 OR 11 OR 12 OR 13 OR 14 OR 15 OR 16 OR 17 OR 18 OR 19 OR 20

23.21 AND 22

24.humans.sh.

25.23 AND 24

1

Appendix 3.Cognitive tests used in the included studies.

1