Therapeutics
Review: Statins do not increase adverse cognitive effects in patients with or without initial cognitive impairment Clinical impact ratings:
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Ott BR, Daiello LA, Dahabreh IJ, et al. Do statins impair cognition? A systematic review and meta-analysis of randomized controlled trials. J Gen Intern Med. 2015;30:348-58.
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Question
Commentary
Do statins increase risk for adverse cognitive effects in patients with or without initial cognitive impairments?
When used in primary prevention, statins reduce all-cause mortality and cardiovascular (CV) events and may reduce risk for dementia (1). Despite these potential benefits, some patients decline or discontinue statins because of anticipated or experienced adverse effects.
Review scope Included studies compared statins approved for use in the USA or Europe (atorvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin) with placebo, no therapy, or standard therapy, and had mean n > 10/group. Outcomes included various measures of cognitive impairment.
Review methods MEDLINE, EMBASE/Excerpta Medica, and CENTRAL (all to Dec 2012); 3 Cochrane reviews, with searches to 2008; a 2013 network meta-analysis; and reference lists were searched for English-language, randomized, controlled trials (RCTs). 25 placebo-controlled RCTs met the selection criteria: 8 evaluated pravastatin, 8 simvastatin, 6 atorvastatin, 6 lovastatin, and 3 rosuvastatin. 18 RCTs (n = 45 564, age range 18 to 86 y) were done in patients without cognitive impairment at baseline, including 12 done in generally healthy participants; 4 (n = 1153, mean age 68 to 78 y) were done in patients with Alzheimer disease; and 3 (n = 119, age range 8 to 50 y) were done in patients with other cognitive impairments. 9 RCTs had adequate allocation concealment; 23 blinded patients, clinicians, and outcome assessors; and 21 had < 20% loss to follow-up.
Main results In patients without cognitive impairment at baseline, statins and placebo did not differ for any cognitive scale score (Table), dementia (2 RCTs, n = 38 338), confusion (1 RCT, n = 17 802), cognitive impairment (1 RCT, n = 20 536), or cognition-related adverse events (1 RCT, n = 17 802). In patients with Alzheimer disease at baseline, statins and placebo did not differ for cognitive scale scores (Table). Results were mixed in RCTs done in patients with other cognitive impairments at baseline.
Conclusion In patients with or without initial cognitive impairment, statins do not increase risk for adverse cognitive effects.
RCTs in healthy persons with normal baseline cognition are most relevant for estimating risk for statin-associated cognitive impairment in primary prevention. In the review by Ott and colleagues, 12 RCTs (n = 1301) were in such patients; however, no separate meta-analysis was done in this group. The JUPITER trial, which included 17 802 generally healthy patients with elevated C-reactive protein levels, was included in the review but not the meta-analysis because it was not designed to assess cognitive function and no specific cognitive testing was done. Instead, meta-analysis of 14 RCTs in persons with normal baseline cognition (n = 27 643) combined data from healthy persons and those with risk factors for CV disease; a separate analysis was done for RCTs of patients with cognitive impairment. Some RCTs in the meta-analysis used instruments specifically vetted to detect statin dyscognition and found small, but statistically significant, adverse effects (2). Some RCTs used dementia screening instruments not calibrated to assess the upper range of cognitive performance most relevant to healthy patients with normal cognition. Thus, some of the RCTs included in the analysis were not designed to answer the question asked by Ott and colleagues, and their results should not deprecate the warning by the US Food and Drug Administration that memory loss, forgetfulness, and confusion have been reported by some statin users. The meta-analysis doesn't adequately address the clinical assessment of patients who are using statins and have cognitive complaints. As one patient with statin dyscognition wrote, “ . . . most depressing of all for a guy in the information technology business, I just wasn't as smart as I used to be” (3). If a knowledge worker using statins complains of difficulty performing intellectually demanding tasks but tests normally on the Modified Telephone Interview for Cognitive Status or similar instrument, are we to ignore his complaint?
The Naranjo Scale is useful for assessing causal associations between drug use and adverse effects (4). Blinded N-of-1 trials may also have a role; they have proven useful for distinguishing For correspondence: Dr. Brian R. Ott, Rhode Island Hospital, statin-associated myalgia from nocebo reaction or other causes, Providence, RI, USA. E-mail [email protected]. with 5 of 8 patients resuming statins when N-of-1 trials found no difference between statins and placebo (5). Physicians should take seriously complaints about statin-associated cognitive impairment, assess alternative causes of dysEffects of statins vs placebo on cognition scale scores* cognition, such as depression or dementia, and consider Naranjo scoring, N-of-1 trials, reduced dosing, or alternaPatients Cognitive function Number of Mean difference tive treatments. or scale assessed trials (n) (95% CI)† Steven M. Belknap, MD, FACP, FCP No baseline cognitive Overall 14 (27 643) 0.01 (⫺0.01 to 0.03) impairment Northwestern University Feinberg School of Medicine Global (≥1 function) 5 (26 515) ⫺0.02 (⫺0.04 to 0.01) Chicago, Illinois, USA Source of funding: Agency for Healthcare Research and Quality.
Alzheimer disease
Executive function
7 (26 926)
0.04 (⫺0.02 to 0.09)
Memory
8 (26 850)
0.00 (⫺0.01 to 0.02)
Processing speed
10 (6630)
0.01 (⫺0.13 to 0.15)
Attention
7 (732)
0.10 (⫺0.17 to 0.37)
Working memory
3 (83)
⫺0.35 (⫺1.24 to 0.55)
Overall
4 (935)
⫺0.05 (⫺0.19 to 0.10)
MMSE
4 (945)
⫺0.67 (⫺1.21 to ⫺0.13)‡
ADAS-Cog
4 (926)
0.97 (⫺2.21 to 4.16)
*ADAS-Cog = Alzheimer's Disease Assessment Scale–Cognition subscale; MMSE = Mini-Mental State Examination; CI defined in Glossary.
5. Joy TR, Monjed A, Zou GY, et al. N-of-1 (single-patient) trials for statin-related myalgia. Ann Intern Med. 2014;160:301-10.
†Mean differences are standardized except for ADAS-Cog and MMSE scales. ‡Not significant after adjustment for multiple comparisons.
姝 2015 American College of Physicians
JC6
References 1. Swiger KJ, Manalac RJ, Blumenthal RS, Blaha MJ, Martin SS. Statins and cognition: a systematic review and meta-analysis of short- and long-term cognitive effects. Mayo Clin Proc. 2013;88:1213-21. 2. Muldoon MF, Ryan CM, Sereika SM, Flory JD, Manuck SB. Randomized trial of the effects of simvastatin on cognitive functioning in hypercholesterolemic adults. Am J Med. 2004;117:823-9. 3. McDonagh J. Statin-related cognitive impairment in the real world: you'll live longer, but you might not like it. JAMA Intern Med. 2014;174: 1889. 4. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981; 30:239-45.
ACP Journal Club
Annals of Internal Medicine
Downloaded From: https://annals.org/pdfaccess.ashx?url=/data/journals/aim/934051/ by a Tufts University User on 07/30/2017
19 May 2015
Review: Statins do not increase adverse cognitive effects in patients with or without initial cognitive impairment Clinical impact ratings:
多多多多多多夞
多多多多多夞夞
多多多多多多夞
Ott BR, Daiello LA, Dahabreh IJ, et al. Do statins impair cognition? A systematic review and meta-analysis of randomized controlled trials. J Gen Intern Med. 2015;30:348-58.
多多多多多多夞
多多多多多多夞
Question
Commentary
Do statins increase risk for adverse cognitive effects in patients with or without initial cognitive impairments?
When used in primary prevention, statins reduce all-cause mortality and cardiovascular (CV) events and may reduce risk for dementia (1). Despite these potential benefits, some patients decline or discontinue statins because of anticipated or experienced adverse effects.
Review scope Included studies compared statins approved for use in the USA or Europe (atorvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin) with placebo, no therapy, or standard therapy, and had mean n > 10/group. Outcomes included various measures of cognitive impairment.
Review methods MEDLINE, EMBASE/Excerpta Medica, and CENTRAL (all to Dec 2012); 3 Cochrane reviews, with searches to 2008; a 2013 network meta-analysis; and reference lists were searched for English-language, randomized, controlled trials (RCTs). 25 placebo-controlled RCTs met the selection criteria: 8 evaluated pravastatin, 8 simvastatin, 6 atorvastatin, 6 lovastatin, and 3 rosuvastatin. 18 RCTs (n = 45 564, age range 18 to 86 y) were done in patients without cognitive impairment at baseline, including 12 done in generally healthy participants; 4 (n = 1153, mean age 68 to 78 y) were done in patients with Alzheimer disease; and 3 (n = 119, age range 8 to 50 y) were done in patients with other cognitive impairments. 9 RCTs had adequate allocation concealment; 23 blinded patients, clinicians, and outcome assessors; and 21 had < 20% loss to follow-up.
Main results In patients without cognitive impairment at baseline, statins and placebo did not differ for any cognitive scale score (Table), dementia (2 RCTs, n = 38 338), confusion (1 RCT, n = 17 802), cognitive impairment (1 RCT, n = 20 536), or cognition-related adverse events (1 RCT, n = 17 802). In patients with Alzheimer disease at baseline, statins and placebo did not differ for cognitive scale scores (Table). Results were mixed in RCTs done in patients with other cognitive impairments at baseline.
Conclusion In patients with or without initial cognitive impairment, statins do not increase risk for adverse cognitive effects.
RCTs in healthy persons with normal baseline cognition are most relevant for estimating risk for statin-associated cognitive impairment in primary prevention. In the review by Ott and colleagues, 12 RCTs (n = 1301) were in such patients; however, no separate meta-analysis was done in this group. The JUPITER trial, which included 17 802 generally healthy patients with elevated C-reactive protein levels, was included in the review but not the meta-analysis because it was not designed to assess cognitive function and no specific cognitive testing was done. Instead, meta-analysis of 14 RCTs in persons with normal baseline cognition (n = 27 643) combined data from healthy persons and those with risk factors for CV disease; a separate analysis was done for RCTs of patients with cognitive impairment. Some RCTs in the meta-analysis used instruments specifically vetted to detect statin dyscognition and found small, but statistically significant, adverse effects (2). Some RCTs used dementia screening instruments not calibrated to assess the upper range of cognitive performance most relevant to healthy patients with normal cognition. Thus, some of the RCTs included in the analysis were not designed to answer the question asked by Ott and colleagues, and their results should not deprecate the warning by the US Food and Drug Administration that memory loss, forgetfulness, and confusion have been reported by some statin users. The meta-analysis doesn't adequately address the clinical assessment of patients who are using statins and have cognitive complaints. As one patient with statin dyscognition wrote, “ . . . most depressing of all for a guy in the information technology business, I just wasn't as smart as I used to be” (3). If a knowledge worker using statins complains of difficulty performing intellectually demanding tasks but tests normally on the Modified Telephone Interview for Cognitive Status or similar instrument, are we to ignore his complaint?
The Naranjo Scale is useful for assessing causal associations between drug use and adverse effects (4). Blinded N-of-1 trials may also have a role; they have proven useful for distinguishing For correspondence: Dr. Brian R. Ott, Rhode Island Hospital, statin-associated myalgia from nocebo reaction or other causes, Providence, RI, USA. E-mail [email protected]. with 5 of 8 patients resuming statins when N-of-1 trials found no difference between statins and placebo (5). Physicians should take seriously complaints about statin-associated cognitive impairment, assess alternative causes of dysEffects of statins vs placebo on cognition scale scores* cognition, such as depression or dementia, and consider Naranjo scoring, N-of-1 trials, reduced dosing, or alternaPatients Cognitive function Number of Mean difference tive treatments. or scale assessed trials (n) (95% CI)† Steven M. Belknap, MD, FACP, FCP No baseline cognitive Overall 14 (27 643) 0.01 (⫺0.01 to 0.03) impairment Northwestern University Feinberg School of Medicine Global (≥1 function) 5 (26 515) ⫺0.02 (⫺0.04 to 0.01) Chicago, Illinois, USA Source of funding: Agency for Healthcare Research and Quality.
Alzheimer disease
Executive function
7 (26 926)
0.04 (⫺0.02 to 0.09)
Memory
8 (26 850)
0.00 (⫺0.01 to 0.02)
Processing speed
10 (6630)
0.01 (⫺0.13 to 0.15)
Attention
7 (732)
0.10 (⫺0.17 to 0.37)
Working memory
3 (83)
⫺0.35 (⫺1.24 to 0.55)
Overall
4 (935)
⫺0.05 (⫺0.19 to 0.10)
MMSE
4 (945)
⫺0.67 (⫺1.21 to ⫺0.13)‡
ADAS-Cog
4 (926)
0.97 (⫺2.21 to 4.16)
*ADAS-Cog = Alzheimer's Disease Assessment Scale–Cognition subscale; MMSE = Mini-Mental State Examination; CI defined in Glossary.
5. Joy TR, Monjed A, Zou GY, et al. N-of-1 (single-patient) trials for statin-related myalgia. Ann Intern Med. 2014;160:301-10.
†Mean differences are standardized except for ADAS-Cog and MMSE scales. ‡Not significant after adjustment for multiple comparisons.
姝 2015 American College of Physicians
JC6
References 1. Swiger KJ, Manalac RJ, Blumenthal RS, Blaha MJ, Martin SS. Statins and cognition: a systematic review and meta-analysis of short- and long-term cognitive effects. Mayo Clin Proc. 2013;88:1213-21. 2. Muldoon MF, Ryan CM, Sereika SM, Flory JD, Manuck SB. Randomized trial of the effects of simvastatin on cognitive functioning in hypercholesterolemic adults. Am J Med. 2004;117:823-9. 3. McDonagh J. Statin-related cognitive impairment in the real world: you'll live longer, but you might not like it. JAMA Intern Med. 2014;174: 1889. 4. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981; 30:239-45.
ACP Journal Club
Annals of Internal Medicine
Downloaded From: https://annals.org/pdfaccess.ashx?url=/data/journals/aim/934051/ by a Tufts University User on 07/30/2017
19 May 2015
