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Chou R, Dana T, Blazina I, et al. Statin Use for the Prevention of Cardiovascular Disease in Adults: A Systematic Review for the U.S. Preventive Services Task Force [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2016 Nov. (Evidence Syntheses, No. 139.)

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  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

Cover of Statin Use for the Prevention of Cardiovascular Disease in Adults

Statin Use for the Prevention of Cardiovascular Disease in Adults: A Systematic Review for the U.S. Preventive Services Task Force [Internet].

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Appendix ADetailed Methods

Appendix A1. Search Strategies

Randomized, Controlled Trials and Controlled Observational Studies

Ovid MEDLINE(R) and Ovid OLDMEDLINE(R) and Cochrane Central Register of Controlled Trials

  1. exp Hydroxymethylglutaryl-CoA Reductase Inhibitors/
  2. (atorvastatin or fluvastatin or lovastatin or pitavastatin or pravastatin or rosuvastatin or simvastatin).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]
  3. (lipitor or lescol or mevacor or livalo or pravachol or crestor or zocor).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]
  4. 2 or 3
  5. 1 or 4
  6. exp Cardiovascular Diseases/
  7. (cardiovascular or coronary or heart or mortality or CHD or CVD).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]
  8. 6 or 7
  9. 5 and 8
  10. Primary Prevention/
  11. prevent$.mp.
  12. 9 and (10 or 11)
  13. limit 12 to humans
  14. limit 13 to English language
  15. limit 13 to abstracts
  16. 14 or 15
  17. limit 16 to (clinical trial, all or clinical trial or comparative study or controlled clinical trial or randomized controlled trial)
  18. 16 and (random$ or control$ or cohort).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]
  19. 17 or 18

Systematic Reviews

Ovid MEDLINE(R) without Revisions

  1. exp Hydroxymethylglutaryl-CoA Reductase Inhibitors/
  2. (atorvastatin or fluvastatin or lovastatin or pitavastatin or pravastatin or rosuvastatin or simvastatin).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]
  3. (lipitor or lescol or mevacor or livalo or pravachol or crestor or zocor).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]
  4. 2 or 3
  5. 1 or 4
  6. exp Cardiovascular Diseases/
  7. (cardiovascular or coronary or heart or mortality or CHD or CVD).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]
  8. 6 or 7
  9. 5 and 8
  10. Primary Prevention/
  11. prevent$.mp.
  12. 9 and (10 or 11)
  13. limit 12 to humans
  14. limit 13 to English language
  15. limit 13 to abstracts
  16. 14 or 15
  17. limit 16 to (meta analysis or systematic reviews)
  18. limit 16 to evidence based medicine reviews
  19. 17 or 18

Cochrane Database of Systematic Reviews

  1. statin$.ti.
  2. limit 1 to full systematic reviews

Appendix A2. Inclusion and Exclusion Criteria

IncludeExclude
Key Question 1. Benefits
PopulationAsymptomatic adults (age ≥40 years) without prior CVD events (e.g., myocardial infarction, angina, revascularization, CVA, or transient ischemic attack), including persons who are at increased risk for CVD events based on 10-year or lifetime individualized CVD risk level or presence of specific CVD risk factorsPopulations in other age groups or with a prior CVD-related event
InterventionsStatinsOther drugs or non-drug interventions (e.g., diet, exercise)
ComparatorsNo treatment or usual care without statinOther comparators not listed as included
OutcomesCHD and/or CVA-related morbidity or mortality; all-cause mortalityIntermediate outcomes (e.g., lipid levels, measures of atherosclerosis such as intima media thickness)
Study DesignRandomized clinical trialsOther study designs
SettingsPrimary care or primary care–generalizableSettings not generalizable to primary care; studies outside the stated timeframe
Key Question 2. Harms
PopulationAsymptomatic adults (age ≥40 years) without prior CVD events (e.g., myocardial infarction, angina, revascularization, CVA, or transient ischemic attack), including persons who are at increased risk for CVD events based on 10-year or lifetime individualized CVD risk level or presence of specific CVD risk factorsPopulations in other age groups or with a prior CVD-related event
InterventionsStatinsOther drugs or non-drug interventions (e.g., diet, exercise)
ComparatorsPlaceboOther comparators not listed as included
OutcomesSide effects from drug interventions, such as myopathy, rhabdomyolysis, myalgia, cognitive loss, diabetes, elevations in liver function tests or creatine phosphokinase levelsAdverse events not related to statin use
Study DesignRandomized clinical trials, and controlled observational studies reporting harmsOther study designs
SettingsPrimary care or primary care–generalizableSettings not generalizable to primary care; studies outside the stated timeframe
Key Question 3. Statin Potency
PopulationAsymptomatic adults (age ≥40 years) without prior CVD events (e.g., myocardial infarction, angina, revascularization, CVA, or transient ischemic attack), including persons who are at increased risk for CVD events based on 10-year or lifetime individualized CVD risk level or presence of specific CVD risk factorsPopulations in other age groups or with a prior CVD-related event
InterventionsStatinsOther drugs or non-drug interventions (e.g., diet, exercise)
ComparatorsHigher vs. lower-potency statin therapyOther comparators not listed as included
OutcomesCHD- and/or CVA-related morbidity or mortality; all-cause mortality. Side effects from drug interventions, such as myopathy, rhabdomyolysis, myalgia, cognitive loss, diabetes, and elevations in liver function tests or creatine phosphokinase levelsOutcomes not listed as included
Study DesignRandomized clinical trialsOther study designs
SettingsPrimary care or primary care–generalizableSettings not generalizable to primary care; studies outside the stated timeframe

Abbreviations: CHD=coronary heart disease; CVA=cardiovascular accident (stroke); CVD=cardiovascular disease; KQ=key question.

Appendix A3. Literature Flow Diagram

Appendix A3 is a literature flow diagram depicting the search and selection of articles for the review. The diagram shows that 3007 abstracts of potentially relevant articles were identified through MEDLINE and Cochrane databases, while 346 articles were reviewed at the full-text level after excluding 2661 nonrelevant abstracts and background articles. From the 346 articles reviewed for inclusion, 291 were excluded. Articles were excluded due to wrong population (34), wrong population due to >10% history of cardiovascular disease at baseline (38), wrong intervention (8), wrong outcomes (46), wrong study design for key question (39), wrong publication type (45), not English language but possibly relevant (3), in systematic review but not directly used (2), wrong comparison (18), abstract only (2), or using original studies instead (56). After excluding these studies, 21 studies in 55 publications were included that provide evidence for the key questions, as follows: 19 trials for Key Question 1a, 0 trials (direct evidence) for Key Question 1b, 7 trials for Key Question 1c, 17 trials and 2 observational studies for Key Question 2, and 3 trials (direct evidence) for Key Question 3.

* Cochrane databases include the Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic Reviews.

† Studies may be included for more than one KQ.

Abbreviations: CHD=coronary heart disease; CVA=cerebrovascular accident; CVD=cardiovascular disease; KQ=key question; LDL-C=low-density lipoprotein cholesterol.

Note: Indirect evidence not shown in figure.

Appendix A4. Excluded Studies With Reasons for Exclusion

Key to Exclusion Codes

Code 3Wrong population
Code 4Wrong intervention
Code 5Wrong outcomes
Code 6Wrong study design for Key Question
Code 7Not a study
Code 8Not English language but possibly relevant
Code 9Wrong population (proportion of patients with prior CVD events at baseline was >10%)
Code 12In systematic review, not directly used
Code 13Wrong comparison
Code 14Using original studies instead (e.g., meta-analysis, compiled study data, or data from another publication)
Code 15Unable to obtain full-text (abstract only)
  1. Baseline risk factors and their association with outcome in the West of Scotland Coronary Prevention Study. The West of Scotland Coronary Prevention Study Group. Am J Cardiol. 1997;79(6):756–62. Exclusion: 6. [PubMed: 9070554]
  2. Compliance and adverse event withdrawal: their impact on the West of Scotland Coronary Prevention Study. Eur Heart J. 1997;18(11):1718–24. Exclusion: 6. [PubMed: 9402445]
  3. Effects of pravastatin in patients with serum total cholesterol levels from 5.2 to 7.8 mmol/liter (200 to 300 mg/dl) plus two additional atherosclerotic risk factors. The Pravastatin Multinational Study Group for Cardiac Risk Patients. Am J Cardiol. 1993;72(14):1031–7. Exclusion: 5. [PubMed: 8213583]
  4. The effects of pravastatin on hospital admission in hypercholesterolemic middle-aged men: West of Scotland Coronary Prevention Study. J Am Coll Cardiol. 1999;33(4):909–15. Exclusion: 5. [PubMed: 10091815]
  5. Influence of pravastatin and plasma lipids on clinical events in the West of Scotland Coronary Prevention Study (WOSCOPS). Circulation. 1998;97(15):1440–5. Exclusion: 6. [PubMed: 9576423]
  6. Pravastatin use and risk of coronary events and cerebral infarction in Japanese men with moderate hypercholesterolemia: the Kyushu Lipid Intervention Study. J Atheroscler Thromb. 2000;7(2):110–21. Exclusion: 13. [PubMed: 11426582]
  7. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med. 1998;339(19):1349–57. Exclusion: 9. [PubMed: 9841303]
  8. Rosuvastatin for cardiovascular prevention: too many uncertainties. Prescrire Int. 2009;18(102):176. Exclusion: 7. [PubMed: 19746571]
  9. Screening experience and baseline characteristics in the West of Scotland Coronary Prevention Study. The WOSCOPS Study Group. West of Scotland Coronary Prevention Study. Am J Cardiol. 1995;76(7):485–91. Exclusion: 5. [PubMed: 7653449]
  10. Afonso L, Veeranna V, Zalawadiya S, et al. Predictors of residual cardiovascular risk in patients on statin therapy for primary prevention. Cardiology. 2011;119(4):187–90. Exclusion: 13. [PMC free article: PMC3221246] [PubMed: 21968436]
  11. Agarwal V, Phung OJ, Tongbram V, et al. Statin use and the prevention of venous thromboembolism: a meta-analysis. Int J Clin Pract. 2010;64(10):1375–83. Exclusion: 14. [PubMed: 20716146]
  12. Alberton M, Wu P, Druyts E, et al. Adverse events associated with individual statin treatments for cardiovascular disease: an indirect comparison meta-analysis. QJM. 2012;105(2):145–57. Exclusion: 14. [PubMed: 21920996]
  13. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). JAMA. 2002;288(23):2998–3007. Exclusion: 9. [PubMed: 12479764]
  14. Amarenco P. Atorvastatin in prevention of stroke and transient ischaemic attack. Expert Opin Pharmacother. 2007;8(16):2789–97. Exclusion: 7. [PubMed: 17956199]
  15. Amarenco P, Benavente O, Goldstein LB, et al. Results of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial by stroke subtypes. Stroke. 2009;40(4):1405–9. Exclusion: 3. [PubMed: 19228842]
  16. Amarenco P, Goldstein LB, Callahan A 3rd, et al. Baseline blood pressure, low- and high-density lipoproteins, and triglycerides and the risk of vascular events in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial. Atherosclerosis. 2009;204(2):515–20. Exclusion: 3. [PubMed: 18962621]
  17. Amarenco P, Goldstein LB, Messig M, et al. Relative and cumulative effects of lipid and blood pressure control in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels trial. Stroke. 2009;40(7):2486–92. Exclusion: 3. [PubMed: 19461031]
  18. Amarenco P, Goldstein LB, Sillesen H, et al. Coronary heart disease risk in patients with stroke or transient ischemic attack and no known coronary heart disease: findings from the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial. Stroke. 2010;41(3):426–30. Exclusion: 3. [PubMed: 20110538]
  19. Amarenco P, Goldstein LB, Szarek M, et al. Effects of intense low-density lipoprotein cholesterol reduction in patients with stroke or transient ischemic attack: the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial. Stroke. 2007;38(12):3198–204. Exclusion: 3. [PubMed: 17962589]
  20. Amarenco P, Labreuche J. Lipid management in the prevention of stroke: review and updated meta-analysis of statins for stroke prevention. Lancet neurol. 2009;8(5):453–63. Exclusion: 14. [PubMed: 19375663]
  21. Amarenco P, Tonkin AM. Statins for stroke prevention: disappointment and hope. Circulation. 2004;109(23 Suppl 1):III44–9. Exclusion: 14. [PubMed: 15198966]
  22. Amarenco P, Tonkin AM. Statins prevent strokes in high-risk patients. J Fam Pract. 2004;53(7):522. Exclusion: 14. [PubMed: 15251087]
  23. Anon. Establishing the benefit of statins in low-to-moderate-risk primary prevention: The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS). Atheroscler Suppl. 2007;8(2 SPEC. ISS.):3–8. Exclusion: 14. [PubMed: 17588826]
  24. Anonymous. Atorvastatin significantly reduces cardiovascular disease and stroke in people with type 2 diabetes. Evidence-based Healthcare & Public Health. 2005;9(1):40–1. Exclusion: 14.
  25. Arad Y, Spadaro LA, Roth M, et al. Treatment of asymptomatic adults with elevated coronary calcium scores with atorvastatin, vitamin C, and vitamin E: the St. Francis Heart Study randomized clinical trial. J Am Coll Cardiol. 2005;46(1):166–72. Exclusion: 4. [PubMed: 15992652]
  26. Arampatzis CA, Goedhart D, Serruys PW, et al. Fluvastatin reduces the impact of diabetes on long-term outcome after coronary intervention--a Lescol Intervention Prevention Study (LIPS) substudy. Am Heart J. 2005;149(2):329–35. Exclusion: 3. [PubMed: 15846273]
  27. Ardigo D, Vaccaro O, Cavalot F, et al. Effectiveness of treat-to-target strategy for LDL-cholesterol control in type 2 diabetes: Post-hoc analysis of data from the MIND.IT study. Eur J Prev Cardiolog. 2014;21(4):456–63. Exclusion: 4. [PubMed: 23147277]
  28. Ardoin SP, Schanberg LE, Sandborg CI, et al. Secondary analysis of APPLE study suggests atorvastatin may reduce atherosclerosis progression in pubertal lupus patients with higher C reactive protein. Ann Rheum Dis. 2014;73(3):557–66. Exclusion: 3. [PMC free article: PMC4104199] [PubMed: 23436914]
  29. Armani A, Toth PP. The CARDS trial: diabetic patients dealt a winning hand. CuRR, Atheroscler Rep. 2006;8(5):429–32. Exclusion: 7. [PubMed: 16901414]
  30. Armani A, Toth PP. SPARCL: the glimmer of statins for stroke risk reduction. CuRR, Atheroscler Rep. 2007;9(5):347–51. Exclusion: 7. [PubMed: 18001616]
  31. Armitage J, Bowman L, Collins R, et al. Effects of simvastatin 40 mg daily on muscle and liver adverse effects in a 5-year randomized placebo-controlled trial in 20,536 high-risk people. BMC Clin Pharmacol. 2009;9:6. Exclusion: 9. [PMC free article: PMC2676245] [PubMed: 19442259]
  32. Arsenault BJ, Barter P, DeMicco DA, et al. Prediction of cardiovascular events in statin-treated stable coronary patients of the treating to new targets randomized controlled trial by lipid and non-lipid biomarkers. PLoS ONE. 2014;9(12) Exclusion: 3. [PMC free article: PMC4273994] [PubMed: 25531109]
  33. Athyros VG, Tziomalos K, Karagiannis A, et al. Atorvastatin: safety and tolerability. Expert Opin Drug Saf. 2010;9(4):667–74. Exclusion: 7. [PubMed: 20553090]
  34. Aung PP, Maxwell HG, Jepson RG, et al. Lipid-lowering for peripheral arterial disease of the lower limb. Cochrane Database Syst Rev. 2007;(4) CD000123. Exclusion: 3. [PMC free article: PMC6823235] [PubMed: 17943736]
  35. Baigent C, Landray M, Leaper C, et al. First United Kingdom Heart and Renal Protection (UK-HARP-I) study: biochemical efficacy and safety of simvastatin and safety of low-dose aspirin in chronic kidney disease. Am J Kidney Dis. 2005;45(3):473–84. Exclusion: 3. [PubMed: 15754269]
  36. Bak AA, Huizer J, Leijten PA, et al. Diet and pravastatin in moderate hypercholesterolaemia: a randomized trial in 215 middle-aged men free from cardiovascular disease. J Intern Med. 1998;244(5):371–8. Exclusion: 5. [PubMed: 9845852]
  37. Ballard KD, Parker BA, Capizzi JA, et al. Increases in creatine kinase with atorvastatin treatment are not associated with decreases in muscular performance. Atherosclerosis. 2013;230(1):121–4. Exclusion: 5. [PMC free article: PMC3779874] [PubMed: 23958263]
  38. Bang CN, Gislason GH, Greve AM, et al. Statins reduce new-onset atrial fibrillation in a first-time myocardial infarction population: a nationwide propensity score-matched study. Eur J Prev Cardiolog. 2014;21(3):330–8. Exclusion: 3. [PubMed: 23012689]
  39. Bang CN, Okin PM. Statin treatment, new-onset diabetes, and other adverse effects: a systematic review. CuRR, Cardiol Rep. 2014;16(3):461. Exclusion: 6. [PubMed: 24464306]
  40. Barylski M, Nikfar S, Mikhailidis DP, et al. Statins decrease all-cause mortality only in CKD patients not requiring dialysis therapy--a meta-analysis of 11 randomized controlled trials involving 21,295 participants. Pharmacol Res. 2013;72:35–44. Exclusion: 14. [PubMed: 23542730]
  41. Barylski M, Nikolic D, Banach M, et al. Statins and new-onset diabetes. CuRR, Pharm Des. 2014;20(22):3657–64. Exclusion: 7. [PubMed: 24040871]
  42. Bays H, Cohen DE, Chalasani N, et al. An assessment by the Statin Liver Safety Task Force: 2014 update. J Clin Lipidol. 2014;8(3 Suppl):S47–57. Exclusion: 7. [PubMed: 24793441]
  43. Beishuizen ED, Jukema JW, Tamsma JT, et al. No effect of statin therapy on silent myocardial ischemia in patients with type 2 diabetes without manifest cardiovascular disease. Diabetes Care. 2005;28(7):1675–9. Exclusion: 14. [PubMed: 15983319]
  44. Bellamy MF, Pellikka PA, Klarich KW, et al. Association of cholesterol levels, hydroxymethylglutaryl coenzyme-A reductase inhibitor treatment, and progression of aortic stenosis in the community. J Am Coll Cardiol. 2002;40(10):1723–30. Exclusion: 6. [PubMed: 12446053]
  45. Berthold HK, Unverdorben S, Zittermann A, et al. Age-dependent effects of atorvastatin on biochemical bone turnover markers: a randomized controlled trial in postmenopausal women. Osteoporos Int. 2004;15(6):459–67. Exclusion: 5. [PubMed: 15205717]
  46. Bjarnason NH, Riis BJ, Christiansen C. The effect of fluvastatin on parameters of bone remodeling. Osteoporos Int. 2001;12(5):380–4. Exclusion: 5. [PubMed: 11444086]
  47. Blankenhorn DH, Azen SP, Kramsch DM, et al. Coronary angiographic changes with lovastatin therapy. The Monitored Atherosclerosis Regression Study (MARS). Ann Intern Med. 1993;119(10):969–76. Exclusion: 9. [PubMed: 8214993]
  48. Blauw GJ, Lagaay AM, Smelt AH, et al. Stroke, statins, and cholesterol. A meta-analysis of randomized, placebo-controlled, double-blind trials with HMG-CoA reductase inhibitors. Stroke. 1997;28(5):946–50. Exclusion: 14. [PubMed: 9158630]
  49. Boekholdt SM, Hovingh GK, Mora S, et al. Very low levels of atherogenic lipoproteins and the risk for cardiovascular events: a meta-analysis of statin trials. J Am Coll Cardiol. 2014;64(5):485–94. Exclusion: 3. [PMC free article: PMC4443441] [PubMed: 25082583]
  50. Bogiatzi C, Hackam DG, McLeod AI, et al. Secular trends in ischemic stroke subtypes and stroke risk factors. Stroke. 2014;45(11):3208–13. Exclusion: 6. [PubMed: 25213343]
  51. Bouchard M-H, Dragomir A, Blais L, et al. Impact of adherence to statins on coronary artery disease in primary prevention. Br J Clin Pharmacol. 2007;63(6):698–708. Exclusion: 13. [PMC free article: PMC2000596] [PubMed: 17214831]
  52. Bradford RH, Shear CL, Chremos AN, et al. Expanded Clinical Evaluation of Lovastatin (EXCEL) study results. I. Efficacy in modifying plasma lipoproteins and adverse event profile in 8245 patients with moderate hypercholesterolemia. Arch Intern Med. 1991;151(1):43–9. Exclusion: 12. [PubMed: 1985608]
  53. Browning JD. Statins and hepatic steatosis: perspectives from the Dallas Heart Study. Hepatology. 2006;44(2):466–71. Exclusion: 5. [PubMed: 16871575]
  54. Bruckert E, Ferrieres J. Evidence supporting primary prevention of cardiovascular diseases with statins: Gaps between updated clinical results and actual practice. Arch Cardiovasc Dis. 2014;107(3):188–200. Exclusion: 7. [PubMed: 24613429]
  55. Bruckert E, Lievre M, Giral P, et al. Short-term efficacy and safety of extended-release fluvastatin in a large cohort of elderly patients. Am J Geriatr Cardiol. 2003;12(4):225–31. Exclusion: 12. [PubMed: 12888702]
  56. Bukkapatnam RN, Gabler NB, Lewis WR. Statins for primary prevention of cardiovascular mortality in women: a systematic review and meta-analysis. Prev Cardiol. 2010;13(2):84–90. Exclusion: 14. [PubMed: 20377811]
  57. Bulbulia R, Bowman L, Wallendszus K, et al. Effects on 11-year mortality and morbidity of lowering LDL cholesterol with simvastatin for about 5 years in 20,536 high-risk individuals: a randomised controlled trial. Lancet. 2011;378(9808):2013–20. Exclusion: 9. [PMC free article: PMC3242163] [PubMed: 22115874]
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  59. Callahan A, Amarenco P, Goldstein LB, et al. Risk of stroke and cardiovascular events after ischemic stroke or transient ischemic attack in patients with type 2 diabetes or metabolic syndrome: secondary analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial. Arch Neurol. 2011;68(10):1245–51. Exclusion: 3. [PubMed: 21670382]
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Appendix A5. USPSTF Quality Rating Criteria

Criteria for Assessing Internal Validity of Individual Studies

The Methods Work Group for the US Preventive Services Task Force (USPSTF) developed a set of criteria by which the internal validity of individual studies could be evaluated. The USPSTF accepted the criteria, and the associated definitions of quality categories, that relate to internal validity at its September 1999 meeting.

This appendix describes the criteria relating to internal validity and the procedures that topic teams follow for all updates and new assessments in making these judgments.

All topic teams use initial “filters” to select studies for review that deal most directly with the question at issue and that are applicable to the population at issue. Thus, studies of any design that use outdated technology or that use technology that is not feasible for primary care practice may be filtered out before the abstraction stage, depending on the topic and the decisions of the topic team. The teams justify such exclusion decisions if there could be reasonable disagreement about this step. The criteria below are meant for those studies that pass this initial filter.

Presented below are a set of minimal criteria for each study design and then a general definition of three categories: “good,” “fair,” and “poor,” based on those criteria. These specifications are not meant to be rigid rules but rather are intended to be general guidelines, and individual exceptions, when explicitly explained and justified, can be made. In general, a “good” study is one that meets all criteria well. A “fair” study is one that does not meet (or it is not clear that it meets) at least one criterion but has no known “fatal flaw.” “Poor” studies have at least one fatal flaw.

Randomized Controlled Trials and Cohort Studies

Criteria

  • Initial assembly of comparable groups:
    • For RCTs: adequate randomization, including first concealment and whether potential confounders were distributed equally among groups.
    • For cohort studies: consideration of potential confounders with either restriction or measurement for adjustment in the analysis; consideration of inception cohorts.
  • Maintenance of comparable groups (includes attrition, cross-overs, adherence, contamination).
  • Important differential loss to follow-up or overall high loss to follow-up.
  • Measurements: equal, reliable, and valid (includes masking of outcome assessment).
  • Clear definition of interventions.
  • All important outcomes considered.
  • Analysis: adjustment for potential confounders for cohort studies, or intention to treat analysis for RCTs.

Definition of ratings based on above criteria

Good: Meets all criteria: Comparable groups are assembled initially and maintained throughout the study (follow-up at least 80 percent); reliable and valid measurement instruments are used and applied equally to the groups; interventions are spelled out clearly; all important outcomes are considered; and appropriate attention to confounders in analysis. In addition, for RCTs, intention to treat analysis is used.

Fair: Studies will be graded “fair” if any or all of the following problems occur, without the fatal flaws noted in the “poor” category below: Generally comparable groups are assembled initially but some question remains whether some (although not major) differences occurred with follow-up; measurement instruments are acceptable (although not the best) and generally applied equally; some but not all important outcomes are considered; and some but not all potential confounders are accounted for. Intention to treat analysis is done for RCTs.

Poor: Studies will be graded “poor” if any of the following fatal flaws exists: Groups assembled initially are not close to being comparable or maintained throughout the study; unreliable or invalid measurement instruments are used or not applied at all equally among groups (including not masking outcome assessment); and key confounders are given little or no attention. For RCTs, intention to treat analysis is lacking.

Source: U.S. Preventive Services Task Force Procedure Manual. Available at: http://www.uspreventiveservicestaskforce.org/uspstf08/methods/procmanual.htm

Appendix A6. Reviewers of the Draft Report

  • Conrad B. Blum, MD
    Professor of Medicine, Columbia University Medical Center
  • John R. Downs, MD (Federal Reviewer)
    Veterans Health Care System
  • Scott Grundy, MD, PhD
    Professor of Internal Medicine, Assistant Chief of Medical Service, University of Texas Southwestern; VA Medical Center, Dallas
  • Rita Redberg, FACC, MSC, MD
    Professor of Medicine, Director of Women's Cardiovascular Services, University of California, San Francisco
  • Paul M. Ridker, MD, MPH
    Professor of Medicine, Harvard Medical School; Director, Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital
  • Neil J. Stone, MD
    Professor of Medicine-Cardiology, Feinberg School of Medicine, Northwestern University
  • Federal Partner
    Veterans Health Administration

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