Therapeutics
Review: Statins do not increase minor or serious symptomatic adverse events in placebo-controlled trials
Finegold JA, Manisty CH, Goldacre B, Barron AJ, Francis DP. What proportion of symptomatic side effects in patients taking statins are genuinely caused by the drug? Systematic review of randomized placebo-controlled trials to aid individual patient choice. Eur J Prev Cardiol. 2014;21:464-74.
Clinical impact ratings: F ★★★★★★✩ C ★★★★★✩✩ e ★★★★★★✩ Question In primary and secondary cardiovascular disease (CVD) prevention, which adverse events (AEs) are associated with use of statins?
Source of funding: No external funding. For correspondence: Dr. J.A. Finegold, National Heart and Lung Institute, London, England, UK. E-mail [email protected]. ■
Review scope
Commentary
Included studies compared statins with placebo for preventing CVD events and reported AEs separately in each group. Studies using nonstatin medications differentially in each group and those done in patients with organ transplants or using renal dialysis were excluded. Outcomes were all-cause mortality, myocardial infarction, stroke, serious AEs (medical events that are fatal, life-threating, or require hospitalization or intervention), other AEs, and treatment withdrawals.
The review by Finegold and colleagues reminds us that statins prevent CV events and death in primary prevention and to a greater extent in secondary prevention. Except for a small increased risk for diabetes in statin users, serious AEs and minor nuisance symptoms were similar in statin and placebo groups. Most statins are generic, and routine testing of liver function is no longer recommended after statin initiation. Statin use, even in primary prevention, is cost-effective (1). Review methods Risk for adverse effects, including diabetes, is slightly greater with MEDLINE and Cochrane Library (to Dec 2012) and systematic high- compared with lower-intensity statin regimens (2). For prireview reference lists were searched for double-blind, randommary prevention with lower-intensity statins, the small risk for ized, controlled trials (RCTs). 29 RCTs (n = 83 880, mean age 55 diabetes is outweighed by reduced CV events when 10-y CVD to 75 y, 48% to 100% men, mean follow-up 0.5 to 6.1 y) met the risk is ≥ 5% (3). Despite the safety and efficacy of statins, > 50% selection criteria: 14 were done in primary and 15 in secondary of patients in usual practice discontinued them, at least temporarprevention settings. Meta-analyses were done for events reported ily, and events attributed to statins occurred in 17% of patients; in > 1 RCT with a total sample size ≥ 500. about 27% of events were myalgias or myopathy (4). Main results Are RCTs missing side effects? It is more likely that most statinSelected meta-analysis results are in the Table. Statins and associated myalgias and other nuisance symptoms are random placebo did not differ for other symptomatic AEs, including suievents and occur just as frequently when patients are not receiving cide, renal disorder, rhabdomyolysis, new cancer, muscle aches, or statins. Physician, pharmacist, and media warnings of potential elevated creatine kinase levels with myopathy symptoms. harm, along with nocebo effects and regression to the mean (improvement after discontinuation), tend to amplify perceptions Conclusion of AEs due to statins. With this in mind, discussions about Statins may increase diabetes in primary cardiovascular disease prevenstatins should shift to preemptively warning patients of future tion but reduce overall mortality and cardiovascular events in primary epiphenomenal myalgias; teach that association does not mean and secondary cardiovascular prevention compared with placebo. causation; and strive to avoid unnecessary discontinuation of statins, particStatins vs placebo in primary or secondary cardiovascular disease prevention* ularly in secondary prevention. Settings Outcomes Number of Weighted Pooled RRR/RRI NNT/NNH (CI) Meera Jain, MD trials (n) event rates (95% CI) Richard Wernick, MD Statins Placebo Providence Portland Medical Center Primary Serious adverse 9 (38 257)‡ 14.8% 14.9% RRR 0.9% (−7 to 8) Not significant Portland, Oregon, USA prevention
events† Treatment withdrawal
Secondary prevention
10 (27 205)‡
12%
13%
RRR 11% (1 to 21)
NNT 67 (37 to 717)
Diabetes
2 (20 640)
2.7%
2.2%
RRI 25% (5 to 48)
NNH 184 (96 to 918)
All-cause mortality
10 (43 124)
3.1%
3.6%
RRR 14% (5 to 23)
NNT 199 (121 to 556)
MI§
8 (37 002)
2.0%
3.0%
Not reported
NNT 100 (72 to 143)
Stroke§
8 (37 002)
0.7%
1.1%
Not reported
NNT 334 (200 to 1000)
Serious adverse events†
5 (14 993)‡
8.3%
11%
RRR 26% (−5 to 48)
Not significant
Treatment withdrawal
9 (22 195)‡
12%
15%
RRR 18% (0 to 33)
Not significant
All-cause mortality
14 (39 080)
13%
14%
RRR 10% (5 to 14)
NNT 70 (50 to 139)
MI§
11 (31 193)
5.8%
8.0%
Not reported
NNT 44 (36 to 59)
Stroke§
7 (27 610)
3.4%
4.1%
Not reported
NNT 143 (84 to 334)
*MI = myocardial infarction; other abbreviations defined in Glossary. Weighted event rates, RRR, RRI, NNT, NNH, and CI calculated from control event rates and odds ratios (random-effects model) in article (serious adverse events and treatment withdrawals) or risk ratios provided by author (diabetes and all-cause mortality). †Medical events that are fatal, life-threatening, or require hospitalization or intervention. ‡Number of patients in analyses provided by author. §Unweighted event rates. NNT calculated from absolute risk differences in article.
15 July 2014 | ACP Journal Club | Volume 161 • Number 2
References 1. Lazar LD, Pletcher MJ, Coxson PG, Bibbins-Domingo K, Goldman L. Cost-effectiveness of statin therapy for primary prevention in a low-cost statin era. Circulation. 2011;124:146-53. 2. Preiss D, Seshasai SR, Welsh P, et al. Risk of incident diabetes with intensivedose compared with moderate-dose statin therapy: a meta-analysis. JAMA. 2011; 305:2556-64. 3. Stone NJ, Robinson JG, Lichtenstein AH, et al; 2013 ACC/AHA Cholesterol Guideline Panel. Treatment of blood cholesterol to reduce atherosclerotic cardiovascular disease risk in adults: synopsis of the 2013 American College of Cardiology/American Heart Association cholesterol guideline. Ann Intern Med. 2014; 160:339-43. 4. Zhang H, Plutzky J, Skentzos S, et al. Discontinuation of statins in routine care settings: a cohort study. Ann Intern Med. 2013;158:526-34.
© 2014 American College of Physicians
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/930510/ by a University of California San Diego User on 04/16/2017
JC3
Review: Statins do not increase minor or serious symptomatic adverse events in placebo-controlled trials
Finegold JA, Manisty CH, Goldacre B, Barron AJ, Francis DP. What proportion of symptomatic side effects in patients taking statins are genuinely caused by the drug? Systematic review of randomized placebo-controlled trials to aid individual patient choice. Eur J Prev Cardiol. 2014;21:464-74.
Clinical impact ratings: F ★★★★★★✩ C ★★★★★✩✩ e ★★★★★★✩ Question In primary and secondary cardiovascular disease (CVD) prevention, which adverse events (AEs) are associated with use of statins?
Source of funding: No external funding. For correspondence: Dr. J.A. Finegold, National Heart and Lung Institute, London, England, UK. E-mail [email protected]. ■
Review scope
Commentary
Included studies compared statins with placebo for preventing CVD events and reported AEs separately in each group. Studies using nonstatin medications differentially in each group and those done in patients with organ transplants or using renal dialysis were excluded. Outcomes were all-cause mortality, myocardial infarction, stroke, serious AEs (medical events that are fatal, life-threating, or require hospitalization or intervention), other AEs, and treatment withdrawals.
The review by Finegold and colleagues reminds us that statins prevent CV events and death in primary prevention and to a greater extent in secondary prevention. Except for a small increased risk for diabetes in statin users, serious AEs and minor nuisance symptoms were similar in statin and placebo groups. Most statins are generic, and routine testing of liver function is no longer recommended after statin initiation. Statin use, even in primary prevention, is cost-effective (1). Review methods Risk for adverse effects, including diabetes, is slightly greater with MEDLINE and Cochrane Library (to Dec 2012) and systematic high- compared with lower-intensity statin regimens (2). For prireview reference lists were searched for double-blind, randommary prevention with lower-intensity statins, the small risk for ized, controlled trials (RCTs). 29 RCTs (n = 83 880, mean age 55 diabetes is outweighed by reduced CV events when 10-y CVD to 75 y, 48% to 100% men, mean follow-up 0.5 to 6.1 y) met the risk is ≥ 5% (3). Despite the safety and efficacy of statins, > 50% selection criteria: 14 were done in primary and 15 in secondary of patients in usual practice discontinued them, at least temporarprevention settings. Meta-analyses were done for events reported ily, and events attributed to statins occurred in 17% of patients; in > 1 RCT with a total sample size ≥ 500. about 27% of events were myalgias or myopathy (4). Main results Are RCTs missing side effects? It is more likely that most statinSelected meta-analysis results are in the Table. Statins and associated myalgias and other nuisance symptoms are random placebo did not differ for other symptomatic AEs, including suievents and occur just as frequently when patients are not receiving cide, renal disorder, rhabdomyolysis, new cancer, muscle aches, or statins. Physician, pharmacist, and media warnings of potential elevated creatine kinase levels with myopathy symptoms. harm, along with nocebo effects and regression to the mean (improvement after discontinuation), tend to amplify perceptions Conclusion of AEs due to statins. With this in mind, discussions about Statins may increase diabetes in primary cardiovascular disease prevenstatins should shift to preemptively warning patients of future tion but reduce overall mortality and cardiovascular events in primary epiphenomenal myalgias; teach that association does not mean and secondary cardiovascular prevention compared with placebo. causation; and strive to avoid unnecessary discontinuation of statins, particStatins vs placebo in primary or secondary cardiovascular disease prevention* ularly in secondary prevention. Settings Outcomes Number of Weighted Pooled RRR/RRI NNT/NNH (CI) Meera Jain, MD trials (n) event rates (95% CI) Richard Wernick, MD Statins Placebo Providence Portland Medical Center Primary Serious adverse 9 (38 257)‡ 14.8% 14.9% RRR 0.9% (−7 to 8) Not significant Portland, Oregon, USA prevention
events† Treatment withdrawal
Secondary prevention
10 (27 205)‡
12%
13%
RRR 11% (1 to 21)
NNT 67 (37 to 717)
Diabetes
2 (20 640)
2.7%
2.2%
RRI 25% (5 to 48)
NNH 184 (96 to 918)
All-cause mortality
10 (43 124)
3.1%
3.6%
RRR 14% (5 to 23)
NNT 199 (121 to 556)
MI§
8 (37 002)
2.0%
3.0%
Not reported
NNT 100 (72 to 143)
Stroke§
8 (37 002)
0.7%
1.1%
Not reported
NNT 334 (200 to 1000)
Serious adverse events†
5 (14 993)‡
8.3%
11%
RRR 26% (−5 to 48)
Not significant
Treatment withdrawal
9 (22 195)‡
12%
15%
RRR 18% (0 to 33)
Not significant
All-cause mortality
14 (39 080)
13%
14%
RRR 10% (5 to 14)
NNT 70 (50 to 139)
MI§
11 (31 193)
5.8%
8.0%
Not reported
NNT 44 (36 to 59)
Stroke§
7 (27 610)
3.4%
4.1%
Not reported
NNT 143 (84 to 334)
*MI = myocardial infarction; other abbreviations defined in Glossary. Weighted event rates, RRR, RRI, NNT, NNH, and CI calculated from control event rates and odds ratios (random-effects model) in article (serious adverse events and treatment withdrawals) or risk ratios provided by author (diabetes and all-cause mortality). †Medical events that are fatal, life-threatening, or require hospitalization or intervention. ‡Number of patients in analyses provided by author. §Unweighted event rates. NNT calculated from absolute risk differences in article.
15 July 2014 | ACP Journal Club | Volume 161 • Number 2
References 1. Lazar LD, Pletcher MJ, Coxson PG, Bibbins-Domingo K, Goldman L. Cost-effectiveness of statin therapy for primary prevention in a low-cost statin era. Circulation. 2011;124:146-53. 2. Preiss D, Seshasai SR, Welsh P, et al. Risk of incident diabetes with intensivedose compared with moderate-dose statin therapy: a meta-analysis. JAMA. 2011; 305:2556-64. 3. Stone NJ, Robinson JG, Lichtenstein AH, et al; 2013 ACC/AHA Cholesterol Guideline Panel. Treatment of blood cholesterol to reduce atherosclerotic cardiovascular disease risk in adults: synopsis of the 2013 American College of Cardiology/American Heart Association cholesterol guideline. Ann Intern Med. 2014; 160:339-43. 4. Zhang H, Plutzky J, Skentzos S, et al. Discontinuation of statins in routine care settings: a cohort study. Ann Intern Med. 2013;158:526-34.
© 2014 American College of Physicians
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/930510/ by a University of California San Diego User on 04/16/2017
JC3
