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Annals of Internal Medicine

Statins and Cognitive Function A Systematic Review Karl Richardson, MD*; Marisa Schoen, BA*; Benjamin French, PhD; Craig A. Umscheid, MD, MSCE; Matthew D. Mitchell, PhD; Steven E. Arnold, MD; Paul A. Heidenreich, MD, MS; Daniel J. Rader, MD; and Emil M. deGoma, MD

Background: Despite the U.S. Food and Drug Administration (FDA) warning regarding cognitive impairment, the relationship between statins and cognition remains unknown. Purpose: To examine the effect of statins on cognition. Data Sources: PubMed, Embase, and Cochrane Library from inception through October 2012; FDA databases from January 1986 through March 2012. Study Selection: Randomized, controlled trials (RCTs) and cohort, case– control, and cross-sectional studies evaluating cognition in patients receiving statins. Data Extraction: Two reviewers extracted data, 1 reviewer assessed study risk of bias, and 1 reviewer checked all assessments. Data Synthesis: Among statin users, low-quality evidence suggested no increased incidence of Alzheimer disease and no difference in cognitive performance related to procedural memory, attention, or motor speed. Moderate-quality evidence suggested no increased incidence of dementia or mild cognitive impairment or any change in cognitive performance related to global cognitive

H

ydroxymethylglutaryl coenzyme A reductase inhibitors (statins) are among the most widely used prescription medications in the United States (1). Large randomized, controlled trials (RCTs) have demonstrated statin-associated relative risk reductions of 20% to 30% for myocardial infarction, 20% for ischemic stroke, and 10% to 15% for all-cause mortality (2). As with all drugs, statins can exert untoward effects, with myopathy being the most well-characterized adverse sequela (3). Recently, a U.S. Food and Drug Administration (FDA) statement formally raised the specter of another potential adverse effect: cognitive impairment. According to a recent poll, cognitive decline ranks second only to cancer among leading health concerns of adults age 45 to 65 years (4). Given the prevalent use of statins, as well as the overwhelming value attached to preserving cognitive function, even a small effect or low incidence of associated cognitive impairment may influence treatment decisions, particularly among individuals at lower risk for atherosclerotic cardiovascular events. Clarifying the relationship between statins and cognitive impairment is therefore critically important both on an

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performance scores, executive function, declarative memory, processing speed, or visuoperception. Examination of the FDA postmarketing surveillance databases revealed a low reporting rate for cognitive-related adverse events with statins that was similar to the rates seen with other commonly prescribed cardiovascular medications. Limitations: The absence of many well-powered RCTs for most outcomes resulted in final strengths of evidence that were low or moderate. Imprecision, inconsistency, and risk of bias also limited the strength of findings. Conclusion: Larger and better-designed studies are needed to draw unequivocal conclusions about the effect of statins on cognition. Published data do not suggest an adverse effect of statins on cognition; however, the strength of available evidence is limited, particularly with regard to high-dose statins. Primary Funding Source: None. Ann Intern Med. 2013;159:688-697. www.annals.org For author affiliations, see end of text. * Dr. Richardson and Ms. Schoen contributed equally to this study.

individual-patient level and from a public health perspective. We conducted a systematic review to examine the association between statin therapy and cognitive function.

METHODS We address the following 2 questions: 1) Does the available published literature demonstrate that statins impair cognitive function? 2) Do the FDA postmarketing surveillance databases suggest a higher risk of cognitiverelated adverse event reports with statins than with other medications commonly prescribed for patients with or at risk for cardiovascular disease? Data Sources and Searches

We searched PubMed, Embase, and the Cochrane Library from inception through October 2012. Bibliographies of included publications were also scanned to identify relevant references. We searched the FDA Spontaneous Reporting System (January 1986 to 1997; data obtained from National Technical Information Service, Washington, DC) and the Adverse Event Reporting System (1997 to March 2012; data obtained from FDAble, Glastonbury, Connecticut) for cases with adverse event reports for which statins were designated as suspect. Search strategies are detailed in Supplement 1, available at www.annals.org. Study Selection

Two reviewers independently screened the PubMed, Embase, and Cochrane Library databases by title and ab-

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Statins and Cognitive Function

stract, and then the full text, to identify RCTs, cohort studies, case– control studies, and cross-sectional studies evaluating cognitive function in adult patients receiving statin therapy. One reviewer queried the FDA adverse event reporting databases. Data Extraction and Quality Assessment

Two reviewers independently extracted data, 1 reviewer assessed each study’s risk of bias, and 1 reviewer checked all assessments. The Cochrane Risk of Bias Assessment Tool was used for RCTs (5), and the Newcastle– Ottawa Scales were used for cohort and case– control studies (6). Data Synthesis and Analysis

We grouped cognitive performance scores reported in RCTs according to the primary cognitive domain or elementary process evaluated by the test. Categories included global cognitive performance, 5 cognitive domains (frontal-executive function and working memory; declarative memory; procedural memory; attention; and processing speed), and 2 elementary processes (visuoperception and motor speed). For cohort, case– control, and cross-sectional studies reporting risk ratios for the incidence of dementia, Alzheimer disease, cognitive impairment without dementia, or mild cognitive impairment, we used the DerSimonian and Laird random-effects model to synthesize the available evidence quantitatively (7). Pooled estimates were calculated by using the fully adjusted risk ratios provided in each publication, with the following 2 exceptions: Unadjusted risk ratios were used when adjusted figures were not provided, and summary estimates were calculated for studies that reported estimates stratified by sex or statin. Withinstudy summary estimates were calculated by using a random-effects model. Random-effects meta-analyses were performed by using the metafor (8) extension package to R 2.15.2 (R Development Core Team, Vienna, Austria). We could not perform meta-analyses of cognitive test results reported in RCTs of patients with intact cognition because of the heterogeneity of outcome measures and inconsistent reporting of effect estimates and measures of uncertainty (that is, SE estimates or CIs). Where data from RCTs or observational studies precluded quantitative synthesis, the results from individual studies were summarized qualitatively. Because risk-of-bias assessment revealed important study limitations, we performed sensitivity analyses restricted to studies at the lowest risk of bias to determine whether the conclusions were being driven by studies at high risk of bias. Studies were considered at the lowest risk of bias if they fulfilled all Cochrane or Newcastle–Ottawa criteria. We assessed the quality of the evidence base for the association between statins and each of the cognitive outcomes using the GRADE (Grading of Recommendations www.annals.org

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Assessment, Development, and Evaluation) approach (9 – 11). The initial GRADE of evidence for each outcome was high if the evidence base included an RCT, low if the evidence base included only observational studies, or very low if the evidence base consisted only of descriptive studies (that is, no control groups). The initial GRADE could then be decreased or increased by 8 criteria. GRADE definitions are as follows and can be interpreted as representing our level of certainty or confidence in the evidence base for the given outcome: 1) High: further research is very unlikely to change confidence in the estimate of effect; 2) Moderate: further research is likely to affect confidence in the estimate of effect and may change the estimate; 3) Low: further research is very likely to affect confidence in the estimate of effect and is likely to change the estimate; 4) Very low: any estimate of effect is very uncertain. To estimate adverse event reporting rates, we divided the number of cases with cognitive-related adverse event reports for statins by the total number of cases of adverse event reports or the total number of prescriptions dispensed. Details are provided in Supplement 2, available at www.annals.org. Adverse event reporting rates were similarly calculated for losartan and clopidogrel. These drugs have not been associated with cognitive impairment despite more than a decade of use, and like statins, are administered to patients with or at high risk for atherothrombotic cardiovascular disease. Role of the Funding Source

This study received no specific external funding.

RESULTS We screened 4157 titles/abstracts and reviewed 124 full-text articles. We included a total of 57 studies (19 RCTs, 26 cohort studies, 6 case– control studies, and 6 cross-sectional studies), of which 27 studies (3 RCTs, 16 cohort, 4 case– control, and 4 cross-sectional) were included in meta-analyses (Figure 1). Four RCTs, 4 cohort studies, and 2 case– control studies met criteria for the lowest risk of bias. For most RCTs, insufficient information was available to judge risk of bias resulting from sequence generation (10 of 19), allocation concealment (10 of 19), or selective outcome reporting (15 of 19). Weaknesses in cohort studies arose from poor representativeness of the cohorts (11 of 26), inadequate follow-up (11 of 26), and limited comparability (8 of 26), most often due to failure to control for level of education. Finally, for case– control studies, exposure ascertainment was limited in 3 of 6 studies because of reliance on self-report or nonblinded interviewers. Table 1 of Supplement 2 (available at www.annals .org) summarizes the number and type of studies, study findings, and GRADE of the quality of the evidence for each cognitive outcome examined. Tables 2 through 4 of Supplement 2 provide a detailed risk-of-bias assessment for each study, including scores for individual risk-of-bias domains. Study design, patient characteristics, and reported 19 November 2013 Annals of Internal Medicine Volume 159 • Number 10 689

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Identification

Figure 1. Summary of evidence search and selection.

Records identified through database searching (n = 4154)

Additional records identified through other sources (n = 3)

Screening

Records identified (n = 4157) Records after duplicates removed (n = 3664)

Records screened (n = 3664)

Citations excluded (n = 3541)

Full-text articles assessed for eligibility (n = 123)

Eligibility

Full-text articles excluded (n = 66) Review articles lacking new data: 4 Duplicate study or subanalysis: 7 No cognitive end point in patients receiving statins: 29 Not applicable to general population: 11 Not randomized or placebo-controlled (for trials): 4 Case reports/series: 11

Included

Articles included in qualitative synthesis (n = 57) RCT: 19 Cohort: 26 Case–control: 6 Cross-sectional: 6

Studies included in quantitative synthesis (n = 27) RCT: 3 Cohort: 16 Case–control: 4 Cross-sectional: 4

RCT ⫽ randomized, controlled trial.

outcomes are provided for RCTs in Tables 5 through 7 of Supplement 2, for cohort and case– control studies in Tables 8, 9, and 12 of Supplement 2, and for crosssectional studies in Tables 10 through 12 of Supplement 2 (all tables are available at www.annals.org). Incidence of Dementia, Alzheimer Disease, or Mild Cognitive Impairment Dementia

Moderate-strength evidence suggested no increased risk for dementia with statins. One RCT at the lowest risk of bias (n ⫽ 20 536) suggested no significant difference in the incidence of all-cause dementia between statin- and placebo-treated patients, although the CI was wide (relative risk [RR], 1.00 [95% CI, 0.61 to 1.64]) (Table 7 of Supplement 2) (12). A meta-analysis of 10 cohort studies (n ⫽ 4 360 137) found that statins were associated with a de-

creased risk for dementia (RR, 0.87 [CI, 0.82 to 0.92]) (Figure 2) (13–22). Of these cohort studies, 1 met criteria for lowest risk of bias (n ⫽ 1560) and demonstrated a reduced risk for dementia among statin users (RR, 0.41 [CI, 0.18 to 0.92]) (20). A meta-analysis of 2 case– control studies (n ⫽ 2679) demonstrated a lower incidence of dementia between statin users (odds ratio [OR], 0.25 [CI, 0.14 to 0.46]) (Figure 3) (23, 24). One case– control study that met criteria for lowest risk of bias (n ⫽ 1364) revealed a similar OR of 0.29 (CI, 0.13 to 0.63) (23). One crosssectional study (n ⫽ 845) showed no significant difference in the prevalence of dementia between statin users and nonusers (OR, 0.54 [CI, 0.22 to 1.33]) (25). One additional case– control study at the lowest risk of bias (n ⫽ 11 039 case-patients and 110 340 controls) examined the association between statin use and hospitalization for de-

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Statins and Cognitive Function

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Figure 2. Meta-analyses of risk ratios from cohort studies for dementia, Alzheimer disease, and mild cognitive impairment. Study, Year (Reference)

Events/Total, n/N Statin Users Nonusers

Adjusted Risk Ratio (95% CI)

466/2798

1.08 (0.77–1.52)

Dementia Rea et al, 2005 (17) Zandi et al, 2005 (13)

8/481

174/2816

1.19 (0.61–2.34)

Szwast et al, 2007 (15)

3/250

29/742

0.31 (0.10–1.00)

Wolozin et al, 2007 (14)*

3361/835 049

3359/394 739

0.73 (0.42–1.27)

Smeeth et al, 2009 (16)

407/129 288

4765/600 241

0.81 (0.71–0.92)

Hippisley-Cox and Coupland, 2010 (19)*

8784/2 004 692

0.89 (0.84–0.94)

Beydoun et al, 2011 (20)

252/1560

0.41 (0.18–0.92)

Parikh et al, 2011 (18)

5316/151 467

0.88 (0.85–0.91)

9264/226 371

Ancelin et al, 2012 (22)*

483/7056

1.01 (0.69–1.48)

Bettermann et al, 2012 (21)

523/2587

0.71 (0.54–0.93) 0.87 (0.82–0.92)

Random-effects model

Alzheimer disease 1.21 (0.77–1.91)

237/2798

Rea et al, 2005 (17) Zandi et al, 2005 (13)

4/481

98/2816

1.19 (0.48–2.96)

Arvanitakis et al, 2008 (30)

16/119

175/810

0.91 (0.54–1.52)

Smeeth et al, 2009 (16)

43/129 288

682/600 241

0.81 (0.55–1.19)

Sparks et al, 2008 (27)

4/727

20/1243

0.33 (0.11–0.98)

Haag et al, 2009 (29)

466/6992

0.57 (0.36–0.90)

Li et al, 2010 (28)

263/3031

0.62 (0.40–0.97)

Beydoun et al, 2011 (20)

178/1561

0.30 (0.09–0.95)

Ancelin et al, 2012 (22)*

332/6859

1.14 (0.85–1.53)

Bettermann et al, 2012 (21)

353/2587

0.69 (0.49–0.97) 0.79 (0.63–0.99)

Random-effects model

Mild cognitive impairment Yaffe et al, 2002 (34)

37/583

42/454

0.67 (0.43–1.05)

Cramer et al, 2008 (35)

28/452

102/1222

0.56 (0.36–0.87)

Sparks et al, 2008 (27)

NA

0.82 (0.48–1.41)

Beydoun et al, 2011 (20)

133/1308

0.71 (0.33–1.52) 0.66 (0.51–0.86)

Random-effects model 0.125

0.250

0.500

Favors Statin Users

1.000

2.000

4.000

Favors Nonusers

NA ⫽ not available. * Pooled analysis as follows: Wolozin et al, 2007: atorvastatin, lovastatin, simvastatin; Hippisley-Cox and Coupland, 2010: atorvastatin/men, atorvastatin/women, fluvastatin/men, fluvastatin/women, pravastatin/men, pravastatin/women, rosuvastatin/men, rosuvastatin/women, simvastatin/men, simvastatin/women; Ancelin et al, 2012: men, women. Adjustments as follows: Rea et al, 2005: age, sex, education, baseline modified Mini-Mental State Examination, cardiovascular disease, cerebrovascular disease, alcohol use; Zandi et al, 2005: age, sex, education, number of ApoE4 alleles, hypertension, diabetes mellitus; Szwast et al, 2007: age, sex, education, ApoE4; Wolozin et al, 2007: age, cardiovascular disease, hypertension, diabetes mellitus, Charlson Index (a measure of chronic disease); Smeeth et al, 2008: age, sex, likelihood of statin use, date of statin initiation, new diagnoses or drug therapies; Hippisley-Cox and Coupland, 2010: age, cardiovascular disease, cerebrovascular disease, diabetes mellitus, depression, use of tricyclic antidepressants or selective serotonin reuptake inhibitors, body mass index; Beydoun et al, 2011: age, sex, race, education, cardiovascular disease, cerebrovascular disease, hypertension, diabetes mellitus, atrial fibrillation, dyslipidemia, body mass index, blood pressure, smoking status; Parikh et al, 2011: medical comorbid conditions defined by the Centers for Medicare & Medicaid Services Hierarchical Condition Categories risk-adjustment model; Ancelin et al, 2012: age, location, education; Bettermann et al, 2012: age, sex, race, education, ApoE4, cardiovascular disease, cerebrovascular disease, baseline mild cognitive impairment, treatment group, location; Sparks, 2008: age, sex, education, ApoE4; Haag et al, 2009: age, sex, education, ApoE4, cardiovascular disease, cerebrovascular disease, diabetes mellitus, other lipid-lowering agents, smoking status, blood pressure, body mass index, total cholesterol; Li et al, 2010: age, cohort, sex, race, education, ApoE4, baseline Cognitive Abilities Screening Instrument, cardiovascular disease, cerebrovascular disease, hypertension, diabetes mellitus, other lipid-lowering agents, smoking status, body mass index; Yaffe et al, 2002: age, education, treatment group, coronary artery bypass grafting, total cholesterol, smoking status; Cramer et al, 2008: education, ApoE4, cerebrovascular disease, diabetes mellitus, smoking status.

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Figure 3. Meta-analyses of risk ratios from case– control studies (top) and cross-sectional studies (bottom) for dementia, Alzheimer disease, and mild cognitive impairment. Study, Year (Reference)

Statin Users/Total, n/N Case Patients

Risk Ratio (95% CI)

Control Patients

Dementia Jick et al, 2000 (23)*

100/1080

12/284

0.29 (0.13–0.63) 0.21 (0.08–0.54)

57/1315

Rockwood et al, 2002 (24)*

0.25 (0.14–0.46)

Random-effects model

Alzheimer disease 0.26 (0.09–0.72)

NA

Rockwood et al, 2002 (24)* Zamrini et al, 2004 (32)*

39/309

466/3088

0.61 (0.43–0.87)

Green et al, 2006 (31)*

23/886

60/1475

0.61 (0.38–0.98) 0.56 (0.41–0.78)

Random-effects model

Mild cognitive impairment Rockwood et al, 2007 (36)*

0.37 (0.16–0.84)

42/1040 0.125

0.250

0.500

1.000

Favors Statin Users

Study, Year (Reference)

2.000

4.000

Favors Nonusers

Events/Total, n/N Statin Users Nonusers

Risk Ratio (95% CI)

Dementia Rodriguez et al, 2002 (25)*

0.54 (0.22–1.33)

170/845

Alzheimer disease Wolozin et al, 2000 (33)

65/10 086

0.45 (0.35–0.58)

666/47 018

Mild cognitive impairment Carisson et al, 2009 (37)

NA

Glasser et al, 2010 (38)*

620/7191

0.84 (0.47–1.49) 0.98 (0.87–1.10)

1338/17 404

0.97 (0.87–1.09)

Random-effects model 0.125

0.250

0.500

Favors Statin Users

1.000

2.000

4.000

Favors Nonusers

NA ⫽ not available. * Adjustments as follows: Jick et al, 2000: age, sex, cardiovascular disease, cerebrovascular disease, hypertension, diabetes mellitus, date of dementia/ Alzheimer disease diagnosis, years of recorded history in General Practice Research Database, practice, body mass index, smoking status; Rockwood et al, 2002: unadjusted results reported; Zamrini et al, 2004: cardiovascular disease, cerebrovascular disease, hypertension, diabetes mellitus, lipid metabolism disorders; Green et al, 2006: age, sex, race, education; Rockwood et al, 2007: sex, education, self-rated health; Rodriguez et al, 2002: age, sex, education, cardiovascular disease, cerebrovascular disease, hypertension, alcohol use, smoking status, primary care physician visit; Wolozin et al, 2000: unadjusted results reported; Carlsson et al, 2009: age, sex, education, mean carotid intima–media thickness; Glasser et al, 2010: age, sex, race, education, income, cardiovascular disease.

mentia and suggested a reduced risk with statins (OR, 0.67 [CI, 0.60 to 0.75]) (26). Alzheimer Disease

Low-strength evidence suggested that statins were not associated with increased risk for Alzheimer disease. No RCTs of statins reported the incidence of Alzheimer disease. A pooled analysis of 10 cohort studies (n ⫽ 759 553) suggested that statins were associated with a decreased risk for Alzheimer disease (RR, 0.79 [CI, 0.63 to 0.99]) (Figure

2) (13, 16, 17, 20 –22, 27–30). A pooled analysis of 3 cohort studies at the lowest risk of bias (n ⫽ 11 584) similarly suggested a lower incidence of Alzheimer disease among statin users (RR, 0.57 [CI, 0.42 to 0.77]) (20, 28, 29). A meta-analysis of 3 case– control studies (n ⬎ 5758) demonstrated a lower incidence of Alzheimer disease among statin users (OR, 0.56 [CI, 0.41 to 0.78]) (Figure 3) (24, 31, 32). One cross-sectional study (n ⫽ 57 104) revealed a lower prevalence of Alzheimer disease among statin users (OR, 0.45 [CI, 0.35 to 0.58]) (33).

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Statins and Cognitive Function Mild Cognitive Impairment or Cognitive Impairment Without Dementia

Moderate-strength evidence suggested that statins did not increase the risk for mild cognitive impairment or cognitive impairment without dementia. One RCT at the lowest risk of bias (n ⫽ 20 536) showed no significant difference in the incidence of mild cognitive impairment between statin- and placebo-treated groups (RR, 0.98 [CI, 0.93 to 1.03]) (Table 7 of Supplement 2) (12). A metaanalysis of 4 cohort studies (n ⬎ 4019) showed a decreased risk for mild cognitive impairment or cognitive impairment without dementia with statin therapy (RR, 0.66 [CI, 0.51 to 0.86]) (Figure 2) (20, 27, 34, 35). Of these cohort studies, 1 met criteria for the lowest risk of bias (n ⫽ 1308) and demonstrated no difference in mild cognitive impairment or cognitive impairment without dementia between statin users and nonusers (RR, 0.71 [CI, 0.33 to 1.52]) (20). One case– control study (n ⫽ 347 case-patients and 693 controls) demonstrated a lower incidence of mild cognitive impairment among statin users (OR, 0.37 [CI, 0.16 to 0.84]) (Figure 3) (36). A meta-analysis of 2 crosssectional studies (n ⬎ 24 595) revealed no difference in the incidence of mild cognitive impairment between statin users and nonusers (OR, 0.97 [CI, 0.87 to 1.09]) (37, 38). Cognitive Performance Scores Global Cognitive Performance in Cognitively Intact Patients

Moderate-strength evidence suggested no worsening of global cognitive performance scores among patients who were cognitively intact at baseline. One RCT at the lowest risk of bias (n ⫽ 5804) demonstrated no significant difference in change in global cognitive performance assessed by Mini-Mental State Examination (MMSE) between statinand placebo-treated patients (0.06 [CI, ⫺0.04 to 0.16]) (Table 1; Table 7 of Supplement 2) (39). Four cohort studies (n ⫽ 7368) (27, 30, 34, 40) showed no difference between statin and placebo groups in end-of-study or change in global cognitive performance evaluated through varied composite scores (Table 10 of Supplement 2). Studies could not be pooled because relevant effect estimates or measures of uncertainty were not reported. Three additional cohort studies (n ⫽ 4688) (15, 21, 41) suggested a significant improvement in global cognitive performance with statin use (Table 10 of Supplement 2). One cross-sectional study (n ⫽ 178) (42) demonstrated better global cognitive performance among statin users than nonusers, but a second study (n ⫽ 548) (43) revealed no difference (Table 10 of Supplement 2). Global Cognitive Performance in Cognitively Impaired Patients

Moderate-strength evidence suggested no worsening of global cognitive performance scores among patients who were cognitively impaired at baseline. Four RCTs (n ⫽ 1127) examined the effect of statins on global cognitive performance among patients with mild to moderate Alzheimer disease (Table 1; Table 7 of Supplement 2) (44 – www.annals.org

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Table 1. Summary of Cognitive Performance Tests in Randomized, Controlled Trials Cognitive Tests, n (%)

Cognitive Domain or Elementary Process Total Global (among cognitively intact) Global (among cognitively impaired) Frontal-executive function and working memory Declarative memory Procedural memory Attention Processing speed Visuoperception Motor speed

No Difference*

Favoring Statin

Favoring Placebo

1

1 (100)

0

0

8

7 (88)

1 (12)

0

30

25 (83)

2 (7)

3 (10)

24 2 31 41 10 8

24 (100) 2 (100) 24 (77) 36 (88) 10 (100) 7 (88)

0 0 2 (6) 2 (5) 0 0

0 0 5 (16) 3 (7) 0 1 (13)

* No statistically significant difference (P ⱖ 0.05) in end-of-treatment or changefrom-baseline scores between statin and placebo groups.

47). A pooled analysis of 3 RCTs (n ⫽ 1064) using the Alzheimer disease Assessment Score–Cognitive Portion (ADAS-Cog) score demonstrated no significant difference in change in cognitive performance (change in score of 0.11 [CI, ⫺1.76 to 1.97]) (44 – 46). A 4-point change in ADAS-Cog score is considered clinically meaningful by expert consensus (48). Of these 4 RCTs, 2 met criteria for the lowest risk of bias (n ⫽ 1020) and similarly showed no significant difference in ADAS-Cog score (44, 45). The MMSE was also assessed in all 4 trials but could not be pooled because relevant estimates were not reported. Three trials described no difference in MMSE scores between statin- and placebo-treated patients (44, 45, 47). One RCT reported significantly better MMSE scores among statintreated patients, with no change observed in the ADASCog score (46). Four cohort studies (n ⫽ 1999) in patients with Alzheimer disease or mild cognitive impairment (49 –52), 1 of which was at the lowest risk of bias (n ⫽ 342) (50), demonstrated no difference in global cognitive performance scores, including MMSE and ADAS-Cog scores, between statin- and placebo-treated patients (Table 10 of Supplement 2). Statin users outperformed nonusers in 3 cohort studies (n ⫽ 605) among populations with Alzheimer disease or those enriched for dementia (53–55). Frontal-Executive Function and Working Memory

Moderate-strength evidence suggested no worsening of cognitive performance related to frontal and executive function and working memory. Seven RCTs (n ⫽ 6497) demonstrated no difference between statin- and placebotreated groups in performance scores of frontal-executive function among most tests (25 of 30) (39, 56 – 61), with a minority of tests indicating better performance scores with statins (2 of 30) (56) or placebo (3 of 30) (59, 60). Among the RCTs, 1 met criteria for the lowest risk of bias (n ⫽ 5804) and revealed no effect of statins on performance on 19 November 2013 Annals of Internal Medicine Volume 159 • Number 10 693

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the Stroop color-word test, a validated test of frontalexecutive function designed to examine the effects of color interference on reading ability (Table 1; Table 7 of Supplement 2) (39). The 1 cohort study identified (n ⫽ 929) demonstrated no significant difference in working memory between statin users and nonusers (Table 10 of Supplement 2) (30). One cross-sectional study (n ⫽ 548) (43) demonstrated superior performance in 2 measures of frontal-executive function among statin users compared with nonusers (Table 10 of Supplement 2). Declarative Memory

Moderate-strength evidence suggested no worsening of cognitive performance related to declarative memory. Eight RCTs (n ⫽ 6434), 1 of which met the criteria for the lowest risk of bias (n ⫽ 5804) (39), demonstrated no significant difference in 24 tests of declarative memory between statin- and placebo-treated patients (Table 1; Table 7 of Supplement 2) (39, 56, 58 – 60, 62– 64). Two cohort studies (n ⫽ 1003) showed no significant difference in 3 measures of declarative memory between statin users and nonusers (Table 10 of Supplement 2) (30, 65). One crosssectional study (n ⫽ 548) (43) found better performance in 2 measures of declarative memory among statin users than nonusers and no difference in 3 tests of declarative memory between the groups (Table 10 of Supplement 2). Procedural Memory

Low-strength evidence suggested no worsening of cognitive performance related to procedural memory. One RCT (n ⫽ 238) demonstrated no significant difference between statin- and placebo-treated patients in 2 tests of procedural memory (Table 1; Table 7 of Supplement 2) (60). The study did not meet criteria for lowest risk of bias. Attention

Low-strength evidence suggested no worsening of cognitive performance related to attention. Among 7 RCTs (n ⫽ 721) (56, 57, 59, 60, 63, 64, 66), most tests (24 of 31) showed no difference between statin- and placebotreated groups (Table 1; Table 7 of Supplement 2). A few tests revealed superior performance among statin users (2 of 31) (57) or placebo-treated groups (5 of 31) (56, 59, 66). No study met criteria for lowest risk of bias.

treated patients by using the Letter Digit Coding Test (39). Two cohort studies (n ⫽ 1003) found no significant difference in 3 measures of processing speed between statin users and nonusers (Table 10 of Supplement 2) (30, 65). One cross-sectional study (n ⫽ 548) (43) found no difference in 2 measures of processing speed between statin users and nonusers (Table 10 of Supplement 2). Visuoperception

Moderate-strength evidence suggested no worsening of cognitive performance related to visuoperception. Four RCTs (n ⫽ 556) revealed no difference in 10 tests of visuoperception between statin- and placebo-treated groups (Table 1; Table 7 of Supplement 2) (56, 58 – 60). One cohort study (n ⫽ 929) found no significant difference in visuoperception between statin users and nonusers (Table 10 of Supplement 2) (30). No study met criteria for lowest risk of bias. Motor Speed

Low-strength evidence suggested no worsening of cognitive performance related to motor speed. Five RCTs (n ⫽ 582) revealed no difference in most performance scores of motor speed (7 of 8) between statin- and placebotreated groups (Table 1; Table 7 of Supplement 2) (56, 59, 60, 63, 64). A single test demonstrated better scores in the placebo-treated group (59). One cohort study (n ⫽ 74) showed no significant difference in motor speed between statin users and nonusers (Table 10 of Supplement 2) (65). No study met criteria for lowest risk of bias. Analysis of the FDA Adverse Event Reporting Databases

Our query of the FDA postmarketing surveillance databases yielded similar cognitive-related adverse event reporting rates for statins (1.9 per million prescriptions) as for losartan (1.6 per million prescriptions) and clopidogrel (1.9 per million prescriptions) (Appendix Table, available at www.annals.org). The proportion of cognitive-related adverse event reports among all submitted reports was also similar among the 3 drugs. Expanding the query to include all drug-associated adverse events (rather than just those for which the drug was listed as suspect) yielded higher reporting rates that remained similar among the 3 drugs (Table 13 of Supplement 2).

Processing Speed

Moderate-strength evidence suggested no worsening of cognitive performance related to processing speed. Thirteen RCTs (n ⫽ 6957) demonstrated no significant difference in most tests (36 of 41) of processing speed (Table 1; Table 7 of Supplement 2) (39, 56 – 61, 63, 64, 66 – 69). A similar number of tests favored statins (2 of 41) (64) or placebo (3 of 41) (59, 60). Among the RCTs, 1 met criteria for the lowest risk of bias (n ⫽ 5804) and showed no difference in processing speed between statin- and placebo-

DISCUSSION Last year, the FDA issued a warning cautioning that statins may be associated with memory loss or confusion. To date, the methods and detailed findings of the FDA’s analysis have not been made available, although 1 report (70) indicated that substantial weight was placed on case reports. Case reports and case series that we identified but ultimately excluded from our systematic review are summarized in Table 14 of Supplement 2 (71– 81). Given the

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implications of possible cognitive impairment with statin use, we systematically evaluated the association of statins and cognitive function (Table 1 of Supplement 2). Among statin users, low-quality evidence suggested no increased incidence of Alzheimer disease and no difference in cognitive performance in procedural memory, attention, or motor speed. Moderate-quality evidence suggested no increased incidence of dementia or mild cognitive impairment, nor any change in cognitive performance related to global cognitive performance scores, executive function, declarative memory, processing speed, or visuoperception. To probe for a potential safety signal, we independently analyzed the FDA postmarketing surveillance databases to calculate reporting rates of cognitive adverse events for statins, losartan, and clopidogrel over the marketed lifetime of these drugs. Reporting rates, calculated as the number of cases of cognitive-related adverse event reports divided by the number of prescriptions dispensed, were similar among the 3 drugs. Of note, neither the angiotensin-receptor blocker nor the P2Y12 adenosine diphosphate–receptor inhibitor has been associated with cognitive impairment. To our knowledge, no studies to date have suggested memory loss with these medications, and the FDA has not issued a formal warning for these drugs. Our systematic review is unique in that it provides the most comprehensive analysis of the literature to date, incorporating substantially more studies than have recent narrative reviews (82), it provides a transparent synthesis of published data organized by cognitive domain, and it provides an independent analysis of the FDA adverse event reporting databases. Our review of the published literature has limitations, which the GRADE approach helped us identify. First, although most end points were informed by multiple studies, the lack of multiple well-powered RCTs for many of these outcomes resulted in final strengths of evidence that were moderate or low. Second, imprecision was of particular concern for several of the cognitive performance outcomes, for which many RCTs were small and used widely varying end points, precluding meta-analyses (83). Third, inconsistency of findings was also of concern for several outcomes, and it remained unclear whether findings were inconsistent because of the increased biases of lesser study designs or differences in tests used to examine our outcomes of interest (for example, for many of the cognitive performance end points) (84). Fourth, the strength of the evidence for our outcomes was limited by the risk of bias of many of the studies informing those evidence bases (85). Insufficient information was available to judge risk of bias resulting from sequence generation, allocation concealment, or selective outcome reporting in most of the available RCTs, and risk-of-bias assessment revealed weaknesses in cohort and case– control studies due to suboptimal representativeness, inadequate follow-up, and poor comparability and exposure ascertainment. Fifth, data are sparse www.annals.org

Review

regarding the cognitive effect of statins at high doses, which is important given the increasing use of high-dose statins for secondary prevention. In addition, to our knowledge, no RCT to date has evaluated the association between rosuvastatin and cognitive function. Interpretation of FDA spontaneous adverse event reports suffers from important limitations as well (86). Absence of adverse event adjudication and incomplete or inaccurate data entry yield low-quality data. In addition, relying on voluntary submission by health care professionals and patients results in underestimation of the true incidence of adverse events due to underreporting. Moreover, causality cannot be inferred from adverse event reports and frequently cannot be formally assessed because of inadequate information. These limitations apply to the analysis of statins as well as the evaluation of losartan and clopidogrel. Despite these limitations, systematic underreporting of adverse events was unlikely to occur with statins compared with the other 2 cardiovascular drugs. Our review identified low- to moderate-quality evidence suggesting a neutral effect on cognitive outcomes. Larger and better-designed studies are needed to draw unequivocal conclusions about the effect of statins on cognition. Published data do not suggest an adverse effect of statins on cognition; however, the strength of available evidence is limited, particularly with regard to high-dose statins. From the Perelman School of Medicine, University of Pennsylvania, and University of Pennsylvania Health System, Philadelphia, Pennsylvania, and Stanford University Medical Center, Stanford, California. Potential Conflicts of Interest: Dr. Arnold: Board membership fees:

TEVA Pharmaceuticals; Grants: National Institutes of Health, Pfizer, Bristol Myers Squibb, Johnson and Johnson, Merck. Dr. Rader: Personal fees: AstraZeneca, Pfizer, Merck. Dr. deGoma: Personal fees: Aegerion; Grants: Pfizer, Amgen, Novartis, Regenerol. All other authors have no disclosures. Disclosures can also be viewed at www.acponline.org /authors/icmje/ConflictOfInterestForms.do?msNum⫽M12-3027. Requests for Single Reprints: Emil M. deGoma, MD, Perelman Center

for Advanced Medicine, Heart and Vascular Center, 3400 Civic Center Boulevard, Philadelphia, PA 19104; e-mail: Emil, [email protected] .edu. Current author addresses and author contributions are available at www.annals.org.

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Author Contributions: Conception and design: K. Richardson, M.

Goma: Heart and Vascular Center, 3400 Civic Center Boulevard, Perelman Center for Advanced Medicine, Philadelphia, PA 19104. Dr. French: 204 Blockley Hall, 423 Guardian Drive, Philadelphia, PA 19104. Drs. Umscheid and Mitchell: 3535 Market Street, Mezzanine, Suite 50, Philadelphia, PA 19104. Dr. Arnold: Penn Memory Center, 3615 Chestnut Street, Philadelphia, PA 19104. Dr. Heidenreich: Veterans Affairs Palo Alto Medical Center, 111C Cardiology, 3801 Miranda Avenue, Palo Alto, CA 94304. Dr. Rader: 11-125 Translational Research Center, 3400 Civic Center Boulevard, Building 421, Philadelphia, PA 19104.

Schoen, C.A. Umscheid, M.D. Mitchell, E.M. deGoma. Analysis and interpretation of the data: K. Richardson, M. Schoen, B. French, C.A. Umscheid, M.D. Mitchell, S.E. Arnold, P.A. Heidenreich, D.J. Rader, E.M. deGoma. Drafting of the article: K. Richardson, M. Schoen, C.A. Umscheid, M.D. Mitchell, E.M. deGoma. Critical revision of the article for important intellectual content: K. Richardson, M. Schoen, B. French, C.A. Umscheid, M.D. Mitchell, S.E. Arnold, P.A. Heidenreich, D.J. Rader, E.M. deGoma. Final approval of the article: K. Richardson, M. Schoen, B. French, C.A. Umscheid, M.D. Mitchell, S.E. Arnold, P.A. Heidenreich, D.J. Rader, E.M. deGoma. Provision of study materials or patients: E.M. deGoma. Statistical expertise: B. French, C.A. Umscheid, M.D. Mitchell. Administrative, technical, or logistic support: K. Richardson, M. Schoen, E.M. deGoma. Collection and assembly of data: K. Richardson, M. Schoen, E.M. deGoma.

Appendix Table. Analysis of U.S. Food and Drug Administration Adverse Event Reports (Suspect) Variable

Statins*

Losartan

Clopidogrel

Date approved Prescriptions dispensed since marketing began, n† Cases of adverse events reported since marketing began, n Cases with cognitive-related adverse events, n‡ Proportion of cognitive-related adverse events, %§ Reporting rate (per 1 million prescriptions)㛳

31 August 1987–12 August 2003 2 180 000 000 307 608 4042 1.3 1.9

14 April 1995 120 000 000 28 186 186 0.7 1.6

17 November 1997 270 000 000 55 586 520 0.9 1.9

* Includes lovastatin (31 August 1987), pravastatin (31 October 1991), simvastatin (23 December 1991), fluvastatin (31 December 1993), atorvastatin (17 December 1996), and rosuvastatin (12 August 2003). † Data are through 31 March 2012. Details on derivation are provided in Supplement 1 (available at www.annals.org). ‡ Details on queries for cases of adverse event reports are provided in Supplement 1. § The proportion of cognitive-related adverse events is the number of cases with suspected cognitive-related adverse event reports divided by the total number of cases of adverse event reports. 㛳 The reporting rate is the number of suspected cases with cognitive-related adverse event reports divided by the number of prescriptions dispensed and is a crude measure of the number of reports received by the U.S. Food and Drug Administration relative to the extent of the use of an agent in the U.S. population.

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19 November 2013 Annals of Internal Medicine Volume 159 • Number 10

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