NLA Task Force on Statin Safety--2014 update.

Abstract

Tabled 1Evidence grading: Strength of recommendation∗The system was adapted as a hybrid of the National Heart Lung and Blood Institutes (NHLBI) rating system (NHLBI cardiovascular-based methodology) used in the new American Heart Association/American College of Cardiology cholesterol guidelines (Stone, 2013) and adapted from the original GRADE system of evidence rating (Guyatt, 2008).GradeStrength of recommendationAStrong recommendationThere is high certainty based on the evidence that the net benefitNet benefit is defined as benefits minus risks/harms of the service/intervention. is substantialBModerate recommendationThere is moderate certainty based on the evidence that the net benefit is moderate to substantial, or there is high certainty that the net benefit is moderateCWeak recommendationThere is at least moderate certainty based on the evidence that there is a small net benefitDRecommend againstThere is at least moderate certainty based on the evidence that it has no net benefit or that the risks/harms outweigh benefitsEExpert opinionThere is insufficient evidence or evidence is unclear or conflicting, but this is what the expert panel recommendsNNo recommendation for or againstThere is insufficient evidence or evidence is unclear or conflicting∗ The system was adapted as a hybrid of the National Heart Lung and Blood Institutes (NHLBI) rating system (NHLBI cardiovascular-based methodology) used in the new American Heart Association/American College of Cardiology cholesterol guidelines (Stone, 2013) and adapted from the original GRADE system of evidence rating (Guyatt, 2008).∗∗ Net benefit is defined as benefits minus risks/harms of the service/intervention. Open table in a new tab Tabled 1Evidence grading: Quality of evidenceTable reprinted with permission.21James P.A. Oparil S. Carter B.L. et al.2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8).JAMA. 2014; 311: 507-520Crossref PubMed Scopus (5848) Google ScholarType of evidenceQuality rating∗The evidence quality rating system used in this guideline was developed by the National Heart, Lung, and Blood Institute's (NHLBI's) Evidence-Based Methodology Lead (with input from NHLBI staff, external methodology team, and guideline panels and work groups) for use by all the NHLBI cardiovascular disease guideline panels and work groups during this project. As a result, it includes the evidence quality rating for many types of studies, including studies that were not used in this guideline. Additional details regarding the evidence quality rating system are available in the online Supplement.Well-designed, well executed RCTs that adequately represent populations to which the results are applied and directly assess effects on health outcomesHighWell-conducted meta-analyses of such studiesHighly certain about the estimate of effect; further research is unlikely to change our confidence in the estimate of effectRCTs with minor limitations affecting confidence in, or applicability of, the resultsModerateWell-designed, well-executed nonrandomized controlled studies and well-designed, well-executed observational studiesWell-conducted meta-analyses of such studiesModerately certain about the estimate of effect; further research may have an impact on our confidence in the estimate of effect and may change the estimateRCTs with major limitationsLowNonrandomized controlled studies and observational studies with major limitations affecting confidence in, or applicability of, the resultsUncontrolled clinical observations without an appropriate comparison group (eg, case series, case reports)Physiological studies in humansMeta-analyses of such studiesLow certainty about the estimate of effect; further research is likely to have an impact on our confidence in the estimate of effect and is likely to change the estimate.RCT, randomized controlled trial.This was the system used in the new American Heart Association/American College of Cardiology cholesterol guidelines3Stone N.J. Robinson J. Lichtenstein A.H. et al.2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines [e-pub ahead of print].J Am Coll Cardiol. 2013; (accessed March 14, 2014)https://doi.org/10.1016/j.jacc.2013.11.002Abstract Full Text Full Text PDF Scopus (3304) Google Scholar, which were published in the 2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults Report from the Panel members appointed to the Eighth Joint National Committee.21James P.A. Oparil S. Carter B.L. et al.2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8).JAMA. 2014; 311: 507-520Crossref PubMed Scopus (5848) Google Scholar∗ The evidence quality rating system used in this guideline was developed by the National Heart, Lung, and Blood Institute's (NHLBI's) Evidence-Based Methodology Lead (with input from NHLBI staff, external methodology team, and guideline panels and work groups) for use by all the NHLBI cardiovascular disease guideline panels and work groups during this project. As a result, it includes the evidence quality rating for many types of studies, including studies that were not used in this guideline. Additional details regarding the evidence quality rating system are available in the online Supplement. Open table in a new tab Statins are the most widely prescribed class of medications in the United States and their benefits for lowering low-density lipoprotein cholesterol (LDL-C) and reducing the risk for coronary heart disease (CHD) are well documented.1Baigent C. Blackwell L. Emberson J. et al.Cholesterol Treatment Trialists (CTT) CollaborationEfficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.Lancet. 2010; 376: 1670-1681Abstract Full Text Full Text PDF PubMed Scopus (4533) Google Scholar Statins have been the cornerstone of pharmacotherapy for the management of high blood cholesterol levels virtually since their development. The American Heart Association /American College of Cardiology 2013 guidelines recently expanded the number of individuals eligible for statin therapy by recommending it for those with: (1) clinical atherosclerotic cardiovascular disease (ASCVD), (2) LDL-C ≥190 mg/dL, (3) type 2 diabetes and age between 40 and 75 years with LDL-C 70 to 189 mg/dL, and (4) an estimated 10-year risk of ASCVD ≥7.5% and age 40 to 75 years.2Goff Jr., D.C. Lloyd-Jones D.M. Bennett G. et al.2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines [e-pub ahead of print].J Am Coll Cardiol. 2013; (Accessed March 14, 2014)https://doi.org/10.1016/j.jacc.2013.11.005Abstract Full Text Full Text PDF PubMed Scopus (1882) Google Scholar, 3Stone N.J. Robinson J. Lichtenstein A.H. et al.2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines [e-pub ahead of print].J Am Coll Cardiol. 2013; (accessed March 14, 2014)https://doi.org/10.1016/j.jacc.2013.11.002Abstract Full Text Full Text PDF Scopus (3304) Google Scholar Considering only those who qualify according to their estimated 10-year risk of ASCVD, it has been reported that of the 101 million people in the United States age 40 to 79 years who do not have cardiovascular disease, 33 million have an estimated 10-year risk of ASCVD ≥7.5%, and another 13 million have a risk between 5% and 7.4%.4Ioannidis J.P. More than a billion people taking statins? Potential implications of the new cardiovascular guidelines.JAMA. 2014; 311: 463-464Crossref PubMed Scopus (164) Google Scholar Using crude global estimates, 920 million people worldwide would be expected to be classified into these risk categories. Although shocking, these numbers do not even account for the hundreds of millions of patients who qualify for statins because they already have ASCVD, diabetes mellitus, or extremely high LDL-C levels. Therefore, the potential risks and benefits of statin use are a major US and worldwide public health concern. RCT, randomized controlled trial. This was the system used in the new American Heart Association/American College of Cardiology cholesterol guidelines3Stone N.J. Robinson J. Lichtenstein A.H. et al.2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines [e-pub ahead of print].J Am Coll Cardiol. 2013; (accessed March 14, 2014)https://doi.org/10.1016/j.jacc.2013.11.002Abstract Full Text Full Text PDF Scopus (3304) Google Scholar, which were published in the 2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults Report from the Panel members appointed to the Eighth Joint National Committee.21James P.A. Oparil S. Carter B.L. et al.2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8).JAMA. 2014; 311: 507-520Crossref PubMed Scopus (5848) Google Scholar In 2006, the National Lipid Association (NLA) convened a Statin Safety Assessment Task Force of experts who published their findings on specific questions related to the muscle, liver, renal, and neurologic effects of statins.5McKenney J.M. Davidson M.H. Jacobson T.A. Guyton J.R. National Lipid Association Statin Safety Assessment Task Force. Final conclusions and recommendations of the National Lipid Association Statin Safety Assessment Task Force.Am J Cardiol. 2006; 97: 89C-94CAbstract Full Text Full Text PDF PubMed Scopus (377) Google Scholar In the period since the report from that Task Force, the body of evidence for the benefits and potential risks of statin use has expanded.6Mancini G.B. Baker S. Bergeron J. et al.Diagnosis, prevention, and management of statin adverse effects and intolerance: proceedings of a Canadian Working Group Consensus Conference.Can J Cardiol. 2011; 27: 635-662Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar, 7Jukema J.W. Cannon C.P. de Craen A.J. Westendorp R.G. Trompet S. The controversies of statin therapy: weighing the evidence.J Am Coll Cardiol. 2012; 60: 875-881Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar, 8Naci H. Brugts J. Ades T. Comparative tolerability and harms of individual statins: a study-level network meta-analysis of 246 955 participants from 135 randomized, controlled trials.Circ Cardiovasc Qual Outcomes. 2013; 6: 390-399Crossref PubMed Scopus (241) Google Scholar Prompted by examination of those data, in 2012, the US Food and Drug Administration (FDA) made new labeling rules that included (1) removal of the routine periodic monitoring of liver enzymes in patients taking statins, recommending instead that liver enzyme tests be performed before statin therapy, and as clinically indicated thereafter; (2) adding information about the potential for generally nonserious and reversible cognitive side effects and reports of increased blood sugar and glycated hemoglobin associated with statin use; and (3) expansion of the contraindications and dose limitations for lovastatin use.9Food and Drug Administration. FDA drug safety communication: important safety label changes to cholesterol lowering statin drugs. Available at: http://www.fda.gov/drugs/drugsafety/ucm293101.htm. Accessed November 6, 2013.Google Scholar This followed an FDA-mandated labeling change in 2011 limiting the use of 80 mg simvastatin to only those patients who have been taking this dose for ≥12 months without evidence of muscle injury, and adding new contraindications and dose limitations for simvastatin with certain medicines.10Food and Drug Administration. FDA drug safety communication: new restrictions, contraindications, and dose limitations for Zocor (simvastatin) to reduce the risk of muscle injury. Available at: http://www.fda.gov/drugs/drugsafety/ucm256581.htm. Accessed January 12, 2014.Google Scholar These labeling changes have raised numerous questions among clinicians regarding the benefits vs risks of statin use and have led to the desire by the leadership of the NLA to convene a new Statin Safety Task Force to update the 2006 review and provide expert panel opinion regarding the issues, which were reviewed in that report, as well as others raised in the interim. In October 2013, a group of experts in the fields of clinical lipidology, diabetes, neurology, hepatology, and myology participated in an NLA Statin Safety Task Force meeting to discuss the available evidence regarding statin safety. The moderators of the Task Force were Dr Terry A. Jacobson (Chair, Emory University, Atlanta, GA), Dr Harold Bays (Louisville Metabolic and Atherosclerosis Research Center, Louisville, KY), Dr Vera Bittner (University of Alabama, Birmingham, AL), Dr John R. Guyton (Duke University, Durham, NC), Dr Kevin C. Maki (Midwest Center for Metabolic & Cardiovascular Research, Chicago, IL), Dr Robert S. Rosenson (Icahn School of Medicine at Mount Sinai, NY, NY), and Dr Peter P. Toth (CGH Medical Center, Sterling, IL). After the full panel met, subpanels developed individual papers on the topics of statin use and (1) cognition, (2) glucose homeostasis and diabetes risk, (3) liver function, (4) muscle-related signs and symptoms, (5) statin intolerance, and (6) interactions with other drugs. These articles were reviewed, edited, and approved by the entire panel. The recommendations represent a consensus of opinions of clinicians considered to be experts in the fields represented by these articles. Most of the evidence evaluated for this report, and, in fact, much of the published evidence for statins, in general, is in the form of clinical trials.6Mancini G.B. Baker S. Bergeron J. et al.Diagnosis, prevention, and management of statin adverse effects and intolerance: proceedings of a Canadian Working Group Consensus Conference.Can J Cardiol. 2011; 27: 635-662Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar, 8Naci H. Brugts J. Ades T. Comparative tolerability and harms of individual statins: a study-level network meta-analysis of 246 955 participants from 135 randomized, controlled trials.Circ Cardiovasc Qual Outcomes. 2013; 6: 390-399Crossref PubMed Scopus (241) Google Scholar The randomized clinical trial is a useful study design for answering questions regarding efficacy, and is, in fact, considered to be at the top of the hierarchy of evidence grading.11Pocock S.J. Clinical Trials: A Practical Approach. John Wiley & Sons, Chicester, UK1983Google Scholar, 12Concato J. Observational versus experimental studies: what's the evidence for a hierarchy?.NeuroRx. 2004; 1: 341-347Crossref PubMed Scopus (140) Google Scholar However, the panel members acknowledge that clinical trials designed primarily to assess efficacy may not be ideal for evaluating adverse effects and potential risks associated with use of a drug.13Vandenbroucke J.P. What is the best evidence for determining harms of medical treatment?.CMAJ. 2006; 174: 645-646Crossref PubMed Scopus (71) Google Scholar, 14Levine M. Ioannidis J. Guyatt G.H. Harm (observational studies).in: Guyatt G. Rennie D. Meade M.O. Cook D.J. JAMA Evidence. Users' Guides to the Medical Literature – A Manual for Evidence-Based Clinical Practice. 2nd ed. McGraw-Hill Global Education Holdings, LLC, New York, NY2008Google Scholar, 15Chou R. Aronson N. Atkins D. et al.AHRQ series paper 4: assessing harms when comparing medical interventions: AHRQ and the effective health-care program.J Clin Epidemiol. 2010; 63: 502-512Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar, 16Department of Health and Human Services, Agency for Healthcare Research and Quality. Methods Guide for Effectiveness and Comparative Effectiveness Reviews, AHRQ Publication No. 10(12)-EHC063–EF2012.Google Scholar, 17Puhan MA, Singh S, Weiss CO, Varadhan R, Sharma R, Boyd CM. Evaluation of the benefits and harms of aspirin for primary prevention of cardiovascular events: a comparison of quantitative approaches. Methods Research Report. (Prepared by Johns Hopkins University Evidence-based Practice Center under contract No. 290-2007-10061-1). Department of Health and Human Services, Agency for Healthcare Research and Quality. AHRQ Publication No. 12(14)-EHC149-EF2013.Google Scholar This is particularly true for adverse effects that (1) occur at a substantially lower frequency than the responses measured for efficacy, (2) may manifest over a period of extended use (ie, a longer period than what is typically captured in clinical trials designed to examine efficacy), (3) occur in subsets of the population that are especially susceptible, and (4) that have multiple causes (other than statins) in the general population. Additionally, the methods used for evaluation of adverse events in clinical trials may not be sensitive enough to capture some signs or symptoms. For example, angiotensin-converting enzyme inhibitor use is associated with a nonproductive cough in approximately 15% of those who take this class of medication,18Dicpinigaitis P.V. Angiotensin-converting enzyme inhibitor-induced cough: ACCP evidence-based clinical practice guidelines.Chest. 2006; 129: 169S-173SCrossref PubMed Scopus (311) Google Scholar but this association was not described until several years after the first drug in this class was approved.19Sesoko S. Kaneko Y. Cough associated with the use of captopril.Arch Intern Med. 1985; 145: 1524Crossref PubMed Scopus (136) Google Scholar One of the major limitations of using randomized controlled trials (RCTs) for the evaluation of safety is that the populations studied are very restricted in their study entry characteristics and often patients with multiple comorbidities and previous statin intolerance are excluded. Thus there is limited generalizability of patients in RCTs compared with the general clinical population, which tends to have more comorbidity and frailty. Examples of exclusions from recent statin RCTs are: pregnancy, reduced renal or hepatic function, on drugs known to affect statin metabolism (ie, cytochrome 3A4 inhibitors, cyclosporine, fibrates, immunosuppressants), advanced age >75 years, uncontrolled diabetes mellitus, congestive heart failure, dementia, cancer, substance abuse, history of noncompliance, and active rheumatologic or musculoskeletal conditions. Thus, patients who are more susceptible to adverse events may be underrepresented in RCTs. In assessing safety or harm of any therapy, going beyond RCTs is thus very important. Evidence needs to be gathered from a broad range of sources, including observational and clinical epidemiologic studies, FDA adverse event reporting systems, meta-analysis of clinical trials, analysis of large health care databases (Veterans Administration, Kaiser, Medicare, other claims databases), and case reports. In assessing harm or safety, the quality of study reports needs to be made explicit beforehand. High-quality studies that assess harm generally prespecify the specific type of harm to be investigated, use “active” vs “passive” inquiry methods about harm, use validated instruments for symptom ascertainment, and evaluate outcomes by a blinded adjudication committee. Often there may be a discrepancy between the reporting of harm from the results of randomized clinical trials compared with that of observational studies. A good example is the low rate of reporting of myalgia in clinical trials using statins vs placebo to that reported in observational studies. The reason for the discrepancy is important and needs to be investigated. Common reasons include distinct biases in study quality, applicability (study population, setting), definition of adverse events, selective reporting of outcomes, and publication bias. These can lead to either a positive or negative bias in determining the true incidence of a reported symptom. The Statin Safety expert panel was charged with the task of addressing specific questions of clinical relevance and to grade the evidence using a hybrid of the National Heart Lung and Blood Institutes (NHLBI) rating system (NHLBI cardiovascular-based methodology), which was adapted from the original Grading of Recommendations Assessment, Development and Evaluation system of evidence rating20Guyatt G.H. Oxman A.D. Vist G.E. et al.GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.BMJ. 2008; 336: 924-926Crossref PubMed Google Scholar and the quality of evidence grading from the new American Heart Association/American College of Cardiology cholesterol guidelines,3Stone N.J. Robinson J. Lichtenstein A.H. et al.2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines [e-pub ahead of print].J Am Coll Cardiol. 2013; (accessed March 14, 2014)https://doi.org/10.1016/j.jacc.2013.11.002Abstract Full Text Full Text PDF Scopus (3304) Google Scholar which were published in the 2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults Report from the Panel members appointed to the Eighth Joint National Committee.21James P.A. Oparil S. Carter B.L. et al.2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8).JAMA. 2014; 311: 507-520Crossref PubMed Scopus (5848) Google Scholar Overall, the Statin Safety Expert Panel reaffirms the general safety of statin therapy. It is the belief of the Panel members that in most patients requiring statin therapy that the potential benefits of statin therapy outweigh the potential risks. In general terms, the number needed to treat in preventing non-fatal myocardial infarction, revascularization, stroke, and CVD mortality, far outweighs the number needed to harm. Because the absolute benefit of statins is related to an individual's baseline risk, it is only in those individuals whose baseline risk is very low that the benefits of statin therapy may not outweigh the risk of adverse events. However to date, based on the Cholesterol Treatment Trialists meta-analysis of 26 clinical trials and 170,000 patients, a value for the concentration of LDL-C or for total CVD risk has not yet been defined that is without relative benefit during statin therapy.1Baigent C. Blackwell L. Emberson J. et al.Cholesterol Treatment Trialists (CTT) CollaborationEfficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.Lancet. 2010; 376: 1670-1681Abstract Full Text Full Text PDF PubMed Scopus (4533) Google Scholar In assessing any patients with real or perceived symptoms related to statins, we first suggest that providers take a patient-centric approach. Any patient complaints related to statins should be taken seriously and appropriately evaluated. It is important to remember that there are multiple causes of symptoms, particularly with musculoskeletal and cognitive complaints, and that a careful history and physical examination is always essential. The true frequency of statin intolerance in the population is unknown, but may approach 10%. Real or perceived symptoms from statins may be an underappreciated cause of nonadherence to therapy. Data from the cross-sectional Understanding Statin use in America and Gaps in Patient Education (USAGE) study suggests that muscle symptoms may occur in up to 29% of patients initiated on statin therapy, and may be an important causal factor for statin discontinuation, statin switching, and statin nonadherence.22Wei M.Y. Ito M.K. Cohen J.D. Brinton E.A. Jacobson T.A. Predictors of statin adherence, switching, and discontinuation in the USAGE survey: understanding the use of statins in America and gaps in patient education.J Clin Lipidol. 2013; 7: 472-483Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar According to the Expert Panel on Statin Intolerance, “the decision on statin intolerance is the patient's decision, based on subjective feelings, preferences, and judgment,” but best when guided “by evaluation and effective communication from the clinician.” The importance of effective and empathetic communication between patient and provider brings back the sentiments of Francis Peabody who once said, “for the secret of the care of the patient is in caring for the patient.”23Oglesby P. The Caring Physician: The Life of Dr. Francis W. Peabody. Francis A. Countway Library of Medicine, Boston, MA1991Google Scholar