PMID- 28476288
OWN - NLM
STAT- MEDLINE
DCOM- 20180924
LR  - 20220321
IS  - 1474-547X (Electronic)
IS  - 0140-6736 (Linking)
VI  - 389
IP  - 10088
DP  - 2017 Jun 24
TI  - Adverse events associated with unblinded, but not with blinded, statin therapy in 
      the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm (ASCOT-LLA): a 
      randomised double-blind placebo-controlled trial and its non-randomised non-blind 
      extension phase.
PG  - 2473-2481
LID - S0140-6736(17)31075-9 [pii]
LID - 10.1016/S0140-6736(17)31075-9 [doi]
AB  - BACKGROUND: In blinded randomised controlled trials, statin therapy has been 
      associated with few adverse events (AEs). By contrast, in observational studies, 
      larger increases in many different AEs have been reported than in blinded trials. 
      METHODS: In the Lipid-Lowering Arm of the Anglo-Scandinavian Cardiac Outcomes 
      Trial, patients aged 40-79 years with hypertension, at least three other 
      cardiovascular risk factors, and fasting total cholesterol concentrations of 6.5 
      mmol/L or lower, and who were not taking a statin or fibrate, had no history of 
      myocardial infarction, and were not being treated for angina were randomly 
      assigned to atorvastatin 10 mg daily or matching placebo in a randomised 
      double-blind placebo-controlled phase. In a subsequent non-randomised non-blind 
      extension phase (initiated because of early termination of the trial because 
      efficacy of atorvastatin was shown), all patients were offered atorvastatin 10 mg 
      daily open label. We classified AEs using the Medical Dictionary for Regulatory 
      Activities. We blindly adjudicated all reports of four prespecified AEs of 
      interest-muscle-related, erectile dysfunction, sleep disturbance, and cognitive 
      impairment-and analysed all remaining AEs grouped by system organ class. Rates of 
      AEs are given as percentages per annum. RESULTS: The blinded randomised phase was 
      done between February, 1998, and December, 2002; we included 101 80 patients in 
      this analysis (5101 [50%] in the atorvastatin group and 5079 [50%] in the placebo 
      group), with a median follow-up of 3.3 years (IQR 2.7-3.7). The non-blinded 
      non-randomised phase was done between December, 2002, and June, 2005; we included 
      9899 patients in this analysis (6409 [65%] atorvastatin users and 3490 [35%] 
      non-users), with a median follow-up of 2.3 years (2.2-2.4). During the blinded 
      phase, muscle-related AEs (298 [2.03% per annum] vs 283 [2.00% per annum]; hazard 
      ratio 1.03 [95% CI 0.88-1.21]; p=0.72) and erectile dysfunction (272 [1.86% per 
      annum] vs 302 [2.14% per annum]; 0.88 [0.75-1.04]; p=0.13) were reported at a 
      similar rate by participants randomly assigned to atorvastatin or placebo. The 
      rate of reports of sleep disturbance was significantly lower among participants 
      assigned atorvastatin than assigned placebo (149 [1.00% per annum] vs 210 [1.46% 
      per annum]; 0.69 [0.56-0.85]; p=0.0005). Too few cases of cognitive impairment 
      were reported for a statistically reliable analysis (31 [0.20% per annum] vs 32 
      [0.22% per annum]; 0.94 [0.57-1.54]; p=0.81). We observed no significant 
      differences in the rates of all other reported AEs, with the exception of an 
      excess of renal and urinary AEs among patients assigned atorvastatin (481 [1.87%] 
      per annum vs 392 [1.51%] per annum; 1.23 [1.08-1.41]; p=0.002). By contrast, 
      during the non-blinded non-randomised phase, muscle-related AEs were reported at 
      a significantly higher rate by participants taking statins than by those who were 
      not (161 [1.26% per annum] vs 124 [1.00% per annum]; 1.41 [1.10-1.79]; p=0.006). 
      We noted no significant differences between statin users and non-users in the 
      rates of other AEs, with the exception of musculoskeletal and connective tissue 
      disorders (992 [8.69% per annum] vs 831 [7.45% per annum]; 1.17 [1.06-1.29]; 
      p=0.001) and blood and lymphatic system disorders (114 [0.88% per annum] vs 80 
      [0.64% per annum]; 1.40 [1.04-1.88]; p=0.03), which were reported more commonly 
      by statin users than by non-users. INTERPRETATION: These analyses illustrate the 
      so-called nocebo effect, with an excess rate of muscle-related AE reports only 
      when patients and their doctors were aware that statin therapy was being used and 
      not when its use was blinded. These results will help assure both physicians and 
      patients that most AEs associated with statins are not causally related to use of 
      the drug and should help counter the adverse effect on public health of 
      exaggerated claims about statin-related side-effects. FUNDING: Pfizer, Servier 
      Research Group, and Leo Laboratories.
CI  - Copyright (c) 2017 Elsevier Ltd. All rights reserved.
FAU - Gupta, Ajay
AU  - Gupta A
AD  - National Heart and Lung Institute, Imperial College London, London, UK; Royal 
      London Hospital, Barts Health NHS Trust, Whitechapel, London, UK; William Harvey 
      Research Institute, Queen Mary University of London, London, UK.
FAU - Thompson, David
AU  - Thompson D
AD  - National Heart and Lung Institute, Imperial College London, London, UK.
FAU - Whitehouse, Andrew
AU  - Whitehouse A
AD  - National Heart and Lung Institute, Imperial College London, London, UK.
FAU - Collier, Tim
AU  - Collier T
AD  - Department of Medical Statistics, London School of Hygiene & Tropical Medicine, 
      London, UK.
FAU - Dahlof, Bjorn
AU  - Dahlof B
AD  - Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska 
      Academy, University of Gothenburg, Gothenburg, Sweden.
FAU - Poulter, Neil
AU  - Poulter N
AD  - Imperial Clinical Trials Unit, Imperial College London, London, UK.
FAU - Collins, Rory
AU  - Collins R
AD  - Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department 
      of Population Health, University of Oxford, Oxford, UK.
FAU - Sever, Peter
AU  - Sever P
AD  - National Heart and Lung Institute, Imperial College London, London, UK. 
      Electronic address: p.sever@imperial.ac.uk.
CN  - ASCOT Investigators
LA  - eng
PT  - Journal Article
PT  - Multicenter Study
PT  - Randomized Controlled Trial
DEP - 20170502
PL  - England
TA  - Lancet
JT  - Lancet (London, England)
JID - 2985213R
RN  - 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors)
RN  - 0 (Hypolipidemic Agents)
RN  - A0JWA85V8F (Atorvastatin)
SB  - IM
CIN - Lancet. 2017 Jun 24;389(10088):2445-2446. PMID: 28476289
CIN - MMW Fortschr Med. 2017 Sep;159(16):40. PMID: 28952088
CIN - Evid Based Med. 2017 Dec;22(6):210. PMID: 29056606
CIN - Lancet. 2017 Oct 21;390(10105):1831-1832. PMID: 29082876
MH  - Adult
MH  - Aged
MH  - Atorvastatin/administration & dosage/*adverse effects
MH  - Double-Blind Method
MH  - Early Termination of Clinical Trials
MH  - Female
MH  - Hematologic Diseases/chemically induced
MH  - Humans
MH  - Hydroxymethylglutaryl-CoA Reductase Inhibitors/*adverse effects
MH  - Hypercholesterolemia/prevention & control
MH  - Hypertension/complications
MH  - Hypolipidemic Agents/administration & dosage/*adverse effects
MH  - Lymphatic Diseases/chemically induced
MH  - Male
MH  - Middle Aged
MH  - Muscular Diseases/chemically induced
MH  - Nocebo Effect
MH  - Risk Factors
MH  - Sleep Wake Disorders
MH  - Treatment Outcome
EDAT- 2017/05/10 06:00
MHDA- 2018/09/25 06:00
CRDT- 2017/05/07 06:00
PHST- 2016/12/20 00:00 [received]
PHST- 2017/02/15 00:00 [revised]
PHST- 2017/02/22 00:00 [accepted]
PHST- 2017/05/10 06:00 [pubmed]
PHST- 2018/09/25 06:00 [medline]
PHST- 2017/05/07 06:00 [entrez]
AID - S0140-6736(17)31075-9 [pii]
AID - 10.1016/S0140-6736(17)31075-9 [doi]
PST - ppublish
SO  - Lancet. 2017 Jun 24;389(10088):2473-2481. doi: 10.1016/S0140-6736(17)31075-9. 
      Epub 2017 May 2.