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An assessment by the Statin Intolerance Panel: 2014 update

      Highlights

      • Statin intolerance requires a patient-centered approach in practice.
      • Statin intolerance might occur in 10% of patients, but true frequency is unknown.
      • Permanent impairment or death from statin use is exceedingly rare.
      • Innovative approaches to research on statin intolerance are needed.

      Abstract

      This article from the National Lipid Association Statin Intolerance Panel provides a framework for understanding statin intolerance and makes general recommendations for health professionals. For specific guidance on adverse events related to muscle, liver, cognition, and glucose metabolism, one should refer to the other reports of the Statin Safety Task Force for those topics. Although statin adverse effects rarely lead to permanent sequelae, symptomatic intolerance frequently hinders cardiovascular risk reduction by statins. We emphasize here the advisory role of the clinician helping each patient to make personal decisions on statin tolerability. We identify a pressing need for further research on statin intolerance and make suggestions for research design.

      Keywords

      Tabled 1Evidence grading: Strength of recommendation
      The system was adapted as a hybrid of the National Heart, Lung, and Blood Institute (NHLBI) rating system (NHLBI cardiovascular-based methodology) used in the new American Heart Association/American College of Cardiology cholesterol guidelines.1 and adapted from the original Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system of evidence rating.2
      GradeStrength of recommendation
      AStrong Recommendation

      There is high certainty based on the evidence that the net benefit
      Net benefit is defined as benefits minus risks/harms of the service/intervention.
      is substantial
      BModerate Recommendation

      There 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 moderate
      CWeak Recommendation

      There is at least moderate certainty based on the evidence that there is a small net benefit
      DRecommend Against

      There is at least moderate certainty based on the evidence that it has no net benefit or that the risks/harms outweigh benefits
      EExpert Opinion

      There is insufficient evidence or evidence is unclear or conflicting, but this is what the expert panel recommends
      NNo Recommendation for or against

      There is insufficient evidence or evidence is unclear or conflicting
      The system was adapted as a hybrid of the National Heart, Lung, and Blood Institute (NHLBI) rating system (NHLBI cardiovascular-based methodology) used in the new American Heart Association/American College of Cardiology cholesterol guidelines.

      Stone NJ, Robinson J, Lichtenstein AH, 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. http://dx.doi.org/10.1016/j.jacc.2013.11.002.

      and adapted from the original Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system of evidence rating.
      • Guyatt G.H.
      • Oxman A.D.
      • Vist G.E.
      • et al.
      GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.
      Net benefit is defined as benefits minus risks/harms of the service/intervention.
      Tabled 1Evidence grading: Quality of evidence
      Table reprinted with permission.
      • James 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).
      Type of evidenceQuality rating
      The evidence quality rating system used in this guideline was developed by the National Heart, Lung, and Blood Institute (NHLBI) 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 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 outcomesHigh
      Well-conducted meta-analyses of such studies
      Highly certain about the estimate of effect; further research is unlikely to change our confidence in the estimate of effect
      RCTs with minor limitations affecting confidence in, or applicability of, the resultsModerate
      Well-designed, well-executed, nonrandomized controlled studies and well-designed, well-executed observational studies
      Well-conducted meta-analyses of such studies
      Moderately certain about the estimate of effect; further research may have an impact on our confidence in the estimate of effect and may change the estimate
      RCTs with major limitationsLow
      Nonrandomized controlled studies and observational studies with major limitations affecting confidence in, or applicability of, the results
      Uncontrolled clinical observations without an appropriate comparison group (eg, case series, case reports)
      Physiological studies in humans
      Meta-analyses of such studies
      Low 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 guidelines

      Stone NJ, Robinson J, Lichtenstein AH, 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. http://dx.doi.org/10.1016/j.jacc.2013.11.002.

      , 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 (JNC 8).
      • James 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).
      The evidence quality rating system used in this guideline was developed by the National Heart, Lung, and Blood Institute (NHLBI) 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 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.
      In 2006, the National Lipid Association (NLA) presented the analysis and recommendations of a Statin Safety Task Force, which clarified issues related to safety of statin drugs. Since then, statin intolerance (adverse effects related to quality of life, leading to decisions to decrease or stop the use of an otherwise-beneficial drug) has come to the forefront of clinical concern, whereas the safety of statins (assessment of potential to cause death or irreversible impairment) has come to be regarded as largely favorable. In this article, we seek to provide a framework for understanding statin intolerance and the roles of patient and clinician in dealing with its manifestations. General recommendations are provided, but this article does not attempt to summarize the conclusions or recommendations of the specific NLA Statin Safety Task Force Panels for muscle, liver, cognition, and diabetes risk. We identify a pressing need for more research on statin intolerance and make suggestions for research design.

      Update on 2006 Statin Safety Task Force report questions

      Several articles in the 2006 Statin Safety Task Force report dealt with the overall safety of statins. Statin benefit in appropriately targeted patients appeared to be orders of magnitude greater than risk with regard to irreversible organ damage and impairment. Benefit-to-risk estimates were even greater with regard to mortality averted from atherosclerotic disease vs mortality (attributable to rhabdomyolysis) associated with statin use.
      • Gotto Jr., A.M.
      Statins, cardiovascular disease, and drug safety.
      • Law M.
      • Rudnicka A.R.
      Statin safety: a systematic review.
      • Guyton J.R.
      Benefit versus risk in statin treatment.
      These assessments of statin safety have not changed in the interim since 2006. What is new since 2006 is a better understanding of how to advise the individual patient with specific adverse effects, ie, statin intolerance.

      2014 Questions

      • 1.
        Does statin intolerance exist?
      ANSWER: Yes.
      STRENGTH OF RECOMMENDATION: A (Strong).
      QUALITY OF EVIDENCE: Moderate.
      EXPLANATION: The Panel strongly recommends that the existence of statin-induced adverse reactions leading to intolerance be recognized. As discussed herein, additional evidence is needed to define the frequency of statin intolerance and to make recommendations for appropriate patient management.
      In the individual case, we define statin intolerance to be adverse symptoms, signs, or laboratory abnormalities attributed by the patient (or provider) to the statin and in most cases perceived by the patient to interfere unacceptably with activities of daily living (such as sleep, work/housework, or leisure-time activity), leading to a decision to stop or reduce statin therapy. Although less likely, the provider might also decide to stop or reduce statin therapy on the basis of clinical/laboratory assessment (abnormal liver function tests, creatine phosphokinase values) suggesting undue risk. We also define statin intolerance for an aggregate population in a stricter sense as clinical or laboratory adverse experiences linked to statin treatment by appropriate scientific evidence and presenting with pain, impairment, or risk–justifying statin cessation or dose reduction. By either definition, our answer to the question “Does statin intolerance exist?” is yes.
      Drug tolerance is related to safety but can be distinguished from it in that intolerance refers to “unpleasant drug-related adverse events without serious or permanent sequelae.”
      • Chou R.
      • Aronson N.
      • Atkins D.
      • et al.
      AHRQ series paper 4: assessing harms when comparing medical interventions: AHRQ and the effective health-care program.
      The distinction often hinges on degree of distress or impairment. In the individual case, the patient's subjective feelings, preferences, and judgment are determinative although best aided by evaluation and effective communication from the clinician. Guidance for the individual case depends on understanding statin intolerance in the population sense. Therefore, we address the stricter population-based definition of statin intolerance here and return to the individual later when considering patient-centered medicine.
      Most statin intolerance is related to myalgia. In rare instances, patients have clinically evident myopathy with weakness and/or markedly increased serum muscle enzymes (myositis, see Muscle Safety Panel Report in this issue for definitions of adverse muscle reactions). Some describe cognitive dysfunction, which usually lacks objective documentation. Adverse effects of statins also include abnormalities in liver enzymes, asymptomatic increase in muscle enzymes, and metabolic derangement associated with risk for new onset of type 2 diabetes mellitus. There is little evidence that statins can induce severe acute liver disease or chronic liver disease. The hepatic enzyme, muscle enzyme, and metabolic abnormalities unquestionably occur, but they are usually asymptomatic, and whether they rise to the level of intolerance requiring cessation or dose reduction depends on a benefit-risk assessment. For most patients appropriately started on statins, mild-to-moderate abnormalities in liver and muscle enzymes, as well as diabetes risk, do not represent serious adverse effects, in that the benefits of proven coronary heart disease reduction with statins outweigh potential risks of laboratory abnormalities. This is discussed in detail by other panels in this updated Statin Safety Task Force report. Cognitive abnormalities are acknowledged but appear to be rare and reversible. This brings us back to the most commonly reported adverse effect associated with statins—myalgia.
      The strongest evidence at present for statin intolerance in the population is the consensus of experienced clinicians that myalgia appears in some patients taking statins, remits with withdrawal, and reoccurs with rechallenge. Our own clinical impressions agree with this consensus. The expert panel strongly affirms that statin intolerance related to myalgia exists, but how frequently it occurs remains of moderate certainty. When faced with patients who complain of myalgia while taking statins, we suggest that the usual burden of proof is reversed. Ordinarily, one must endeavor to prove that a drug exerts an effect, but this is strictly true only for purported beneficial effects to support clinical use of the drug. In the situation of a drug-associated adverse reaction, whether or not it might be overreported by patients, the burden for the medical community is to prove that it does not exist or that its real frequency lies below a certain small level.
      The incidence of reported statin intolerance is widely variable and dependent upon how the intolerance was assessed and the setting. Some might argue that the greater reported rates of statin intolerance are driven by the media. However, within a few years after the introduction of statins for clinical use, one clinic reported that 5% of their patients prescribed simvastatin stopped within 6 months because of perceived adverse reactions, and overall 14%, most of whom continued treatment, described myalgia.
      • Scott R.S.
      • Lintott C.J.
      • Wilson M.J.
      Simvastatin and side effects.
      As early as 1995, Shepherd suggested that lovastatin might induce some kind of myopathy “with or without elevation of muscle enzyme levels” in approximately 5% of patients.
      • Shepherd J.
      Fibrates and statins in the treatment of hyperlipidaemia: an appraisal of their efficacy and safety.
      These early reports were unlikely to have been influenced by media or internet attention to muscle reactions.
      In contrast to these clinically based reports, randomized clinical trials of statins with large numbers of subjects have not shown significant differences in the number of subjects reporting muscle symptoms between statin- and placebo-allocated groups.
      • Collins R.
      • Armitage J.
      • Parish S.
      • Sleigh P.
      • Peto R.
      MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial.
      The challenge here is that some randomized trials dropped patients with muscle or other complaints during the lead-in before randomization. Also, common exclusion criteria for entry into a statin clinical trial have been a previous history of statin intolerance and being on other medications known to increase statin blood levels. Thus, although it may seem paradoxical, clinical trial results obtained thus far are unlikely to assess the frequency of statin intolerance accurately. A definitive study would recruit patients who report myalgia associated with statin use and then randomize them to double-blind statin vs placebo. Surprisingly, after 26 years of clinical availability of statins, definitive trials remain to be performed, as we discuss later in this article.
      • 2.
        Are statins generally well tolerated and safe?
      ANSWER: Yes.
      STRENGTH OF RECOMMENDATION: A (Strong).
      QUALITY OF EVIDENCE: High.
      EXPLANATION: The risk for mortality or permanent organ damage associated with statins is very small. Mortality risk is almost entirely related to rhabdomyolysis. Between 1987 and 2001, the US Food and Drug Administration received 42 reports of deaths from rhabdomyolysis associated with the use of statins excluding cerivastatin, which is an average of 3 reported deaths per year.
      • Staffa J.A.
      • Chang J.
      • Green L.
      Cerivastatin and reports of fatal rhabdomyolysis.
      In a study of claims data from managed health care plans between 1998 and 2001, the rate of rhabdomyolysis in hospitalized patients treated with simvastatin, pravastatin, or atorvastatin was 4.4 per 100,000 person-years.
      • Graham D.J.
      • Staffa J.A.
      • Shatin D.
      • et al.
      Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs.
      Randomized clinical trials reported a similar rate, but rhabdomyolysis also occurred among those assigned to placebo.
      • Law M.
      • Rudnicka A.R.
      Statin safety: a systematic review.
      Some cases arose from drug interactions and were avoidable. The case fatality rate for hospitalized rhabdomyolysis was about 1 in 10.
      • Law M.
      • Rudnicka A.R.
      Statin safety: a systematic review.
      Therefore, mortality caused by statin treatment is rare. In contrast, the benefit of statin use is to avoid several hundred deaths and several hundred cases each of heart and brain infarction per 100,000 patients treated.
      No effect of statin treatment on cancer incidence or mortality was evident in a meta-analysis of individual data from 175,000 patients in 27 randomized clinical trials of statins. The negative results apply to 23 separate anatomic sites and also to the subset of participants with baseline low-density lipoprotein cholesterol (LDL-C) <2 mmol/L (77 mg/dL).
      • Emberson J.R.
      • Kearney P.M.
      • Blackwell L.
      • et al.
      Cholesterol Treatment Trialists (CTT) Collaboration
      Lack of effect of lowering LDL cholesterol on cancer: meta-analysis of individual data from 175,000 people in 27 randomised trials of statin therapy.
      Increased incidence of type 2 diabetes mellitus is a relatively newly identified statin adverse effect whose frequency is mainly increased in those with other elements of the metabolic syndrome or prediabetes such as obesity, glucose intolerance, and hypertension. It is unclear whether this effect is reversible with statin discontinuation or after weight loss with diet and exercise. It is clear, however, that the benefits from statins as measured by the number needed to treat for a reduction in myocardial infarction and stroke is much more favorable than the number needed to harm from incident diabetes. This is described in detail by the Diabetes Safety Panel.
      Statins are among the safest drugs used in medical practice. No evidence to the contrary has arisen from observational data or clinical trials. Long-term follow-up studies of randomized clinical trials ranging from 10 to 15 years support the safety of statins.
      • Ford I.
      • Murray H.
      • Packard C.J.
      • Shepherd J.
      • Macfarlane P.W.
      • Cobbe S.M.
      West of Scotland Coronary Prevention Study Group
      Long-term follow-up of the West of Scotland Coronary Prevention Study.
      • Bulbulia R.
      • Bowman L.
      • Wallendszus K.
      • et al.
      Heart Protection Study Collaborative Group
      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.
      Individual patients have taken statins at relatively high doses over periods of 25+ years without discernible adverse effects.
      • 3.
        Do large randomized trials provide reliable estimates of statin intolerance?
      ANSWER: No.
      STRENGTH OF RECOMMENDATION: E, Expert Opinion.
      QUALITY OF EVIDENCE: Low.
      EXPLANATION: Well-designed clinical trials provide reliable results for their primary end points, which are generally efficacy end points and, to a much lesser degree, for their prespecified secondary end points, which often include safety end points. Statin tolerability appears far down the list of end points in most randomized clinical trials. The sole exception is a trial of 420 subjects reported very recently by Parker et al.
      • Parker B.A.
      • Capizzi J.A.
      • Grimaldi A.S.
      • et al.
      Effect of statins on skeletal muscle function.
      with a primary end point of statin-associated myalgia. Clinical trials often exclude patients with co-morbid conditions that might affect tolerability. Patients who enroll in statin trials begin with a self-assessment of health sufficiently robust to take on the extra effort of trial visits and lifestyle and medication adherence. Retention in clinical trials and maintenance of study medications is actively encouraged. Apart from the study by Parker et al.,
      • Parker B.A.
      • Capizzi J.A.
      • Grimaldi A.S.
      • et al.
      Effect of statins on skeletal muscle function.
      end points related to statin intolerance, such as myalgia or other muscle symptoms, usually have been assessed only by spontaneous reporting as adverse events and not by targeted questions to monitor these symptoms.
      Two large clinical trials included specific monitoring for statin adverse effects. The Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) performed cognitive and disability assessments as tertiary end points. Pravastatin did not change the rate of decrease of cognitive function and did not affect disability scores.
      • Shepherd J.
      • Blauw G.J.
      • Murphy M.B.
      • et al.
      PROSPER study group. PROspective Study of Pravastatin in the Elderly at Risk
      Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial.
      The Heart Protection Study (HPS) specifically recorded “new unexplained muscle pain or weakness” at postrandomization visits.
      MRC/BHF Heart Protection Study of cholesterol-lowering therapy and of antioxidant vitamin supplementation in a wide range of patients at increased risk of coronary heart disease death: early safety and efficacy experience.
      Although muscle complaints were common at 6% for any given visit, the fraction of subjects ever reporting them was exactly the same at 33% in both the simvastatin- and placebo-assigned groups. During the prerandomization run-in phase of HPS that included 4 weeks of placebo followed by 4 to 6 weeks of simvastatin 40 mg, 36% of potential subjects were dropped before randomization. However, less than 3% had adverse symptoms from simvastatin as the reason for stopping.
      • Armitage J.
      • Bowman L.
      • Collins R.
      • Parish S.
      • Tobert J.
      MRC/BHF Heart Protection Study Collaborative Group
      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.
      These data suggest an upper limit for simvastatin-related muscle reactions well below the level of 10.5% described in the Prediction of Muscular Risk in Observational Studies (PRIMO),
      • Bruckert E.
      • Hayem G.
      • Dejager S.
      • Yau C.
      • Begaud B.
      Mild-to-moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients—the PRIMO study.
      but the upper limit in HPS applies only to people similar to those who volunteer for a clinical trial. Interestingly, among individuals in HPS who attended the first randomization visit but were not randomized, 15.4% reported new unexplained muscle symptoms in response to active inquiry.
      • Armitage J.
      • Bowman L.
      • Collins R.
      • Parish S.
      • Tobert J.
      MRC/BHF Heart Protection Study Collaborative Group
      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.
      Thus, active inquiry led to a greater percentage of patients being excluded from the trial and thus may have led to an underestimation of statin-related muscle symptoms during the trial. An internet-based survey reported muscle-related adverse events in 29% of 10,138 current and former statin users.
      • Cohen J.D.
      • Brinton E.A.
      • Ito M.K.
      • Jacobson T.A.
      Understanding Statin Use in America and Gaps in Patient Education (USAGE): an internet-based survey of 10,138 current and former statin users.
      The respondents for this survey were drawn from 27,946 hypercholesterolemic individuals in an online-registered multinational consumer panel. Clearly, reports of muscle side effects among statin users in practice are relatively frequent compared with the 3% limit at the outset of HPS.
      There is a continuing need for observational studies of statin intolerance. We also call attention to the need for randomized, double-blind trials that extend the work of Parker et al.,
      • Parker B.A.
      • Capizzi J.A.
      • Grimaldi A.S.
      • et al.
      Effect of statins on skeletal muscle function.
      examining statin intolerance as a primary end point with innovative approaches for subject enrollment and pre-randomization evaluation (see below).
      One of the more challenging aspects of determining the frequency of statin intolerance is the absence of a validated clinical scale. Validated scales for assessment of the tolerability of other lipid-altering drugs have been proposed and tested. It is surprising that no similar tolerance instrument has yet been developed for statins, which is by far the most widely used lipid-altering drug class. The Muscle Safety Panel report in this issue proposes a statin myalgia index, which needs to be validated in a prospective clinical trial.
      • 4.
        Is statin intolerance best defined in the context of patient-centered medicine?
      ANSWER: Yes.
      STRENGTH OF RECOMMENDATION: E, (Expert Opinion).
      QUALITY OF EVIDENCE: Not Applicable.
      EXPLANATION: In its recent formulation of standards for trustworthy clinical practice guidelines, the Institute of Medicine reaffirmed the fundamental role of scientific evidence for clinical practice, then added the following qualifying statement: “At the same time, and particularly under conditions of uncertainty regarding optimal decisions, clinician experiential knowledge and skill (the “art of medicine”) and patient values and preferences remain essential contributors to quality healthcare practice, in a complex interplay with science.”
      This is best exemplified by the recent concepts of “patient centered medicine”
      • Bardes C.L.
      Defining “patient-centered medicine”.
      • Walsh M.N.
      • Bove A.A.
      • Cross R.R.
      • et al.
      American College of Cardiology Foundation
      ACCF 2012 health policy statement on patient-centered care in cardiovascular medicine: a report of the American College of Cardiology Foundation Clinical Quality Committee.
      and the importance of “shared decision making.”
      • Barry M.J.
      • Edgman-Levitan S.
      Shared decision making—pinnacle of patient-centered care.
      Levenstein et al.
      • Levenstein J.H.
      • McCracken E.C.
      • McWhinney I.R.
      • Stewart M.A.
      • Brown J.B.
      The patient-centred clinical method. 1. A model for the doctor-patient interaction in family medicine.
      suggested that the health care provider must manage 2 parallel agendas in pursuit of patient-centered medicine. The clinician's own agenda is to make a diagnosis via history and objective data. The clinician must also evaluate the patient's agenda, which includes expectations, feelings, and fears. The 2 agendas merge in a joint process of deciding on further observation, evaluation, or treatment. In the context of statin-associated muscle reactions, the role of patient-centered medicine is further emphasized by the subjective nature of the problem. As reviewed in this supplement by the Muscle Safety Panel, the role of objective data in dealing with muscle reactions is very limited. The agenda for the clinician is to advise and support the patient in his or her decision to continue, terminate, or change treatment for the lipid disorder.
      • 5.
        Is it safe to advise a patient to continue statin therapy even when some degree of statin intolerance is present?
      ANSWER: Yes.
      STRENGTH OF RECOMMENDATION: B, Moderate.
      QUALITY OF EVIDENCE: Low.
      EXPLANATION: A common perception among patients is that a person should stop any medication to which an “allergy” has developed. Although this is true in some cases—for example, a typical drug rash occurring after the administration of penicillin or allopurinol—the development of a mild symptomatic muscle reaction or occasional difficulty recalling a name should not necessarily lead to discontinuation of statin treatment. It may be necessary for the clinician to educate the patient, letting him or her know that the potential adverse reaction, even if caused by the statin, is not a true allergic response but rather a manifestation of individual sensitivity to the drug (ie, an idiosyncratic reaction, excepting, of course, urticarial or other classic allergic reactions, which are rare with statins).
      The decision for or against continuing to take a statin sometimes can be simplified by casting it as a question of tolerance (ie, how bothersome are the symptoms?) rather than a question of diagnosis (ie, are the symptoms really due to the statin?). The latter question is often very difficult to answer in the individual case.
      This kind of patient-centered approach again supports the need for validated scales for statin intolerance, which incorporate assessments of the degree to which the potential bothersome aspects of statin therapy affect the daily lives of patients. These would be similar to those often assessed in quality-of-life scales by recording and measuring the effect on work/housework and leisure time activity, and the degree to which perceived adverse effects influenced the willingness of patients to persist with statin treatment.
      An example of tolerable symptoms that might not lead to statin discontinuation would be the development of mild leg stiffness on rising in the morning, which lasts for 30–60 minutes and does not interfere with daily activities. At the other extreme, statin-induced muscle weakness can lead to an inability to rise from a chair unaided by hands and arms or to difficulty walking up stairs. We cannot conceive of a benefit from statin use that would outweigh such weakness, especially if confirmed by dechallenge and rechallenge. Most patients with adverse effects related to statins present with symptoms between the extremes described above. Estimation of the relative harm vs benefit, and deference to patient values and preferences, comprise the dual agenda for the clinician who practices patient-centered medicine. In general, continuation of the statin can often be advised when symptoms are mild and last only a short portion of the day, and when daily activities, occupational endeavors, sleep, and recreational and exercise routines are not compromised.
      • 6.
        Are recommendations for widespread use of statins to prevent atherosclerotic cardiovascular disease appropriate, given the emerging evidence with regard to statin intolerance?
      ANSWER: Yes.
      STRENGTH OF RECOMMENDATION: A (Strong).
      QUALITY OF EVIDENCE: High.
      EXPLANATION: We reaffirm the conclusions of established guidelines that call for widespread use of statins to treat patients with increased risk for atherosclerotic cardiovascular disease.

      Stone NJ, Robinson J, Lichtenstein AH, 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. http://dx.doi.org/10.1016/j.jacc.2013.11.002.

      Expert Panel on Detection E, Treatment of High Blood Cholesterol in Adults
      Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III).
      • Grundy S.M.
      • Cleeman J.I.
      • Merz C.N.
      • et al.
      National Heart Lung, Blood Institute, American College of Cardiology Foundation, American Heart Association
      Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines.

      Goff DC, Jr., Lloyd-Jones DM, 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. http://dx.doi.org/10.1016/j.jacc.2013.11.005.

      During the past 9 years, new large randomized trials have added to the data confirming efficacy and safety of statin use (Stroke Prevention by Aggressive Reduction in Cholesterol Levels [SPARCL], Incremental Decrease in End points through Aggressive Lipid lowering [IDEAL], and Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin [JUPITER]).
      • Amarenco P.
      • Bogousslavsky J.
      • Callahan 3rd, A.
      • et al.
      Stroke Prevention by Aggressive Reduction in Cholesterol Levels I
      High-dose atorvastatin after stroke or transient ischemic attack.
      • Pedersen T.R.
      • Faergeman O.
      • Kastelein J.J.
      • et al.
      Incremental Decrease in End Points Through Aggressive Lipid Lowering Study G
      High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial.
      • Ridker P.M.
      • Danielson E.
      • Fonseca F.A.
      • et al.
      Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein.
      Although a prospective observational study estimated the prevalence of statin intolerance as high as 10%–15%,
      • Bruckert E.
      • Hayem G.
      • Dejager S.
      • Yau C.
      • Begaud B.
      Mild-to-moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients—the PRIMO study.
      • Cohen J.D.
      • Brinton E.A.
      • Ito M.K.
      • Jacobson T.A.
      Understanding Statin Use in America and Gaps in Patient Education (USAGE): an internet-based survey of 10,138 current and former statin users.
      such high rates have not been seen in randomized clinical trials. Even if the higher estimates apply, at least 85% of patients will still have the benefits of statin therapy. Overemphasis on statin intolerance can hinder appropriate clinical use of a drug that greatly ameliorates the impact of atherosclerotic vascular disease.
      • 7.
        Are there clinical trial designs that may reliably address questions of statin intolerance?
      ANSWER: Yes.
      STRENGTH OF RECOMMENDATION: E, Expert Opinion.
      QUALITY OF EVIDENCE: Not Applicable.
      EXPLANATION: Research questions needing attention relate (1) to the frequency, severity, and impact on daily activities of statin adverse effects; and (2) to alternative strategies for reaching lipid treatment goals in statin-intolerant patients.
      Observational studies of real-world clinical use of statins and randomized, placebo-controlled, double-blind clinical trials provide complementary information on the frequency and impact of statin intolerance. Both strategies should continue to be implemented. Randomized trials give definitive evaluation of the relationship between drug exposure and adverse effects, whereas observational studies test the applicability of results to actual clinical use. In both kinds of studies, the use of genetic testing for the common SLCO1B1*5 mutation (∼15% of alleles, ∼28% of patients) and other genetic variants may provide the opportunity to test hypotheses via Mendelian randomization.
      • Voora D.
      • Shah S.H.
      • Spasojevic I.
      • et al.
      The SLCO1B1*5 genetic variant is associated with statin-induced side effects.
      Certain elements of design should be included in randomized trials, if clear answers on statin intolerance are to be obtained. First, statin tolerance/intolerance must be the primary end point. Second, the comparison should include blinded statin vs placebo medication. An active comparator is not mandatory in atherosclerosis prevention trials lasting 1 to 6 months, depending on clinical scenario.
      • Stone N.J.
      Stopping statins.
      Third, investigators are encouraged to consider recruiting subjects with a personal history of statin intolerance to provide sufficient statistical power at reasonable cost.
      The most straightforward study design is the parallel group comparison (Fig. 1A). This type of comparison offers the least-complex interpretation and may be preferred for that reason. Alternatives to the parallel group comparison are study designs in which every subject receives a statin at some point in the trial. Fewer subjects are needed, but the variability of the drug-placebo sequence introduces potential confounding. From the point of view of a prospective research study, these “crossover” designs offer to each individual a probable answer with regard to statin intolerance. This could help recruitment and give the advantage of focusing the trial on the group of patients who want to discover if their symptoms are truly related to statin treatment. The traditional crossover design (Fig. 1B) could heighten the attention of subjects to symptoms in the period immediately after commencement of study drug vs placebo, because these times are known to the subject. A variation on the crossover trial design introduces the real statin drug at an unknown, randomly chosen time within the overall study period (Fig. 1C). By providing a placebo run-in period of variable and unknown length, this type of design might reduce the role of anxiety and focused attention on determining study results.
      Figure thumbnail gr1
      Figure 1Three types of randomized trial designs for statin-intolerance studies: (A) Parallel group; (B) Crossover; and (C) Crossover with variable time of treatment onset. In each panel, patients are assumed to be randomly assigned. Open bars, placebo treatment. Solid bars, statin treatment.
      The other broad issue for new research is the testing of alternative strategies for lipid treatment when statin intolerance is recognized. Examples of research questions in this category include the following:
      • a.
        Can low-dose statin combined with nonstatin drugs achieve the goals of therapy with regard to either lipid-lowering or clinical outcomes?
      • b.
        Can nonstatin drugs in combination achieve the goals of therapy?
      • c.
        Can different statin regimens achieve the goals of therapy in statin-intolerant patients?
      In targeting these research questions toward goals of therapy, some complexity of goals must be recognized. The ideal of recruiting statin-intolerant subjects for large randomized clinical trials with clinical cardiovascular end points is probably not feasible at this time. Surrogate end points will be necessary, of which the best may be LDL-C, non–high-density lipoprotein-cholesterol, or some measure of molar concentration of LDL particles (either apolipoprotein B or a physically derived measure such as nuclear magnetic resonance particle concentrations). A validated index of statin intolerance should also be included among study end points.
      • 8.
        Is there a universally accepted definition of statin intolerance that can be used by clinicians, researchers, insurers, and regulatory authorities?
      ANSWER: No.
      STRENGTH OF RECOMMENDATION: E, Expert Opinion.
      QUALITY OF EVIDENCE: Low.
      EXPLANATION: The lack of standard definition(s) for statin intolerance has made it difficult for clinicians, researchers, and regulatory agencies to communicate effectively about such a widespread and important clinical and public health issue. A basic dilemma, which we addressed in the discussion following Question #1, is that statin intolerance should be defined differently for the individual case (perspective of the patient and the treating clinician) and for a population of treated individuals (research perspective). For the individual case, the patient's judgment to discontinue the drug is determinative, although best guided by counsel from the provider. From the population or research perspective, randomized, blinded, placebo-controlled challenge trials are required, without discounting the complementary value of continuing observational studies.
      There remains a need, however, for a pragmatic definition that will mediate between the research and the individual perspectives described previously. A pragmatic definition will help the clinician provide accurate and helpful advice to the patient. Ultimately a validated clinical scale, which will be based on research results, will be part of the definition.
      At present, clinicians, regulatory agencies, and insurers (federal and private) may benefit from a provisional definition of statin intolerance that may allow for better communication and research. For this purpose, the NLA Expert Panel on Statin Intolerance proposes the following definition:Statin intolerance is a clinical syndrome characterized by the inability to tolerate at least 2 statins: one statin at the lowest starting daily dose AND another statin at any daily dose, due to either objectionable symptoms (real or perceived) or abnormal lab determinations, which are temporally related to statin treatment and reversible upon statin discontinuation, but reproducible by re-challenge with other known determinants being excluded (such as hypothyroidism, interacting drugs, concurrent illnesses, significant changes in physical activity or exercise, and underlying muscle disease). Specifically, the lowest starting statin daily dose, is defined as rosuvastatin 5 mg, atorvastatin 10 mg, simvastatin 10 mg, lovastatin 20 mg, pravastatin 40 mg, fluvastatin 40 mg, and pitavastatin 2 mg.
      A further question is whether degrees of statin intolerance should be proposed. One might consider “complete statin intolerance” to be the inability to tolerate the lowest daily recommended starting dose of at least 1 statin, plus the aforementioned conditions. Such a definition of complete statin intolerance, however, has some limitations. First, some statins dosed on a non-daily basis at their lowest recommended starting dose, eg, atorvastatin 10 mg or rosuvastatin 5–10 mg taken 2 or 3 days a week—may achieve LDL-C lowering comparable with or better than that of oral non-statin drugs.
      • Keating A.J.
      • Campbell K.B.
      • Guyton J.R.
      Intermittent nondaily dosing strategies in patients with previous statin-induced myopathy.
      Second, nondaily statin doses have not been studied in randomized clinical trials, and, thus, the evidence base for their clinical benefit is lacking.

      Recommendations from the Statin Intolerance Expert Panel

      Recommendations to clinicians

      • 1.
        The clinician should acknowledge that statin intolerance is a real phenomenon, manifesting mostly as an array of muscle-related symptoms that include aching, stiffness, proximal motor weakness, fatigue, and back pain. Estimates of the frequency of muscle symptoms verifiably related to statin use range from 1% to 10%. Severe myopathy with objective weakness and/or markedly elevated muscle enzymes is rare. Reliable research designs are only beginning to address the actual frequency of statin muscle intolerance in populations.
      • 2.
        Cognitive difficulties while taking statins continue to be reported by a small number of patients, but objective documentation of impaired cognition is generally lacking. No evidence points toward progressive or permanent impairment of cognition induced by statins. The frequency of cognitive difficulties is unknown, but is clearly much lower than that of muscle symptoms.
      • 3.
        Statin treatment results in substantial increases in serum hepatic transaminase levels (alanine aminotransferase and/or aspartate aminotransferase increases >3 times the upper limit of normal) in 0.3%–3% of patients in a dose-dependent manner. However, evidence does not support the concerns that statins may seriously impair the metabolic functions of the liver acutely, or that statins may induce cumulative damage to liver cells leading to chronic liver disease. Baseline determination of liver function before statin initiation is recommended, but regular monitoring of hepatic transaminase levels in statin-treated patients is no longer recommended.
      • 4.
        The use of statins is associated with increased risk for new-onset diabetes mellitus, especially when greater doses of statins are used. However, the magnitude of increased risk is small compared with other diabetes risk factors such as obesity. Moreover, the benefit of proven coronary heart disease reduction with statins outweighs the risk of new-onset diabetes.
      • 5.
        In every individual case, the decision on statin intolerance is the patient's decision, based on subjective feelings, preferences, and judgment, although it is best aided by evaluation and effective communication from the clinician.
      • 6.
        Statin intolerance usually does not involve substantial risk for mortality or permanent disability. Therefore, the clinician should help the patient distinguish statin intolerance from “drug allergy,” which could imply substantial risk with any drug rechallenge. The question for statin rechallenge, usually with modified dosing, may be best presented as a question of tolerance (How bothersome are the symptoms?) rather than a question of diagnosis (Are the symptoms really due to the statin?). The latter question is often too difficult to answer for an individual patient.
      • 7.
        Based on the foregoing considerations, we recommend that the clinician and patient attempt to maintain statin treatment in some form in almost every case of statin intolerance. In a large observational study of routine clinical practice, the fraction of patients who reported muscle symptoms with high doses of statins (as currently recommended) was about 10%. In that study, the muscle symptoms generally led to changes in lipid-lowering therapy. Most of such patients can be continued on statin treatment, commonly with doses and/or alternative statins that achieve a lower degree of LDL-C lowering than initially targeted. Because of the logarithmic dose response for LDL-C lowering, statins taken at 4-fold lower doses or even less can often achieve clinically meaningful LDL-C reductions. Atorvastatin or rosuvastatin at doses of 5–10 mg taken once or twice a week may reduce LDL-C by 16%–26%.
      • 8.
        The clinician may optionally pursue nonstatin treatment of high LDL-C or non–high-density lipoprotein in statin-intolerant patients, with or without concomitant statin therapy, based mainly on the probable inferences that LDL is causally involved in atherosclerosis and that LDL-C–lowering is the major mechanism of cardiovascular event reduction by statins. Options to be considered include bile acid sequestrants, niacin, ezetimibe, fibrates, plant sterol esters or stanol esters (formulated in margarines), viscous fiber (such as that found in oat bran, legumes, and psyllium), and substitution of mono- or polyunsaturated fats for trans unsaturated or saturated fats in the diet. Of the nonstatin therapies, those agents that have proven cardiovascular outcome data should be considered first.
      • 9.
        Specific recommendations for many issues of statin intolerance related to muscle, liver, cognition, and diabetes risk can be found in the reports of the Statin Safety Task Force Panels addressing those topics.

      Recommendations to patients

      • 1.
        Taking a statin is one of the most effective ways to lower your risk of atherosclerosis, a disease of arteries in which cholesterol builds up in the arterial wall. Atherosclerosis is a silent disease that usually develops without any symptoms until instability of the inner lining of arteries leads to the sudden appearance of a blood clot, causing a heart attack or stroke. Almost every adult in the United States has atherosclerosis to some extent. At least 1 in 3 people over their lifetime will experience a heart attack or stroke that kills the person or damages heart or brain. This is the reason that statins are recommended for so many people.
      • 2.
        About 1 in 10 people who try taking a statin will report some kind of intolerance, most commonly muscle aches in the legs, trunk, or shoulders and upper arms. Statins can cause weakness or muscle breakdown (which has caused a few deaths), but these effects are rare compared with muscle aches. The prevention of death and disability from improving atherosclerosis is far greater than the risk from taking a statin.
      • 3.
        A few people have reported memory lapses or difficulty with their thinking while taking a statin. This is much less frequent than muscle problems. In older people, most problems with memory or thinking are caused by something else. Careful observation and clinical trials suggest that statins do not contribute to the common problem of dementia in older people. If you experience memory or thinking problems, you and your health care provider will want to carefully consider whether stopping your statin drug is worth the increased risk for heart attack and stroke.
      • 4.
        Although abnormal blood tests for liver enzymes develop in as many as 1 in 30 people taking high-dose statins, there is little evidence that statins damage the liver or block essential functions of the liver. In the past, regulatory agencies such as the US Food and Drug Administration recommended that blood tests for liver enzymes be checked while taking statins, but this recommendation has been withdrawn, and no monitoring is needed. Your health care provider may still want to check liver tests before or at the time of starting statin treatment, or if you have symptoms suggesting a liver problem.
      • 5.
        People taking statins have a small increase in their risk for developing diabetes mellitus with high blood sugar. However, the benefit of reducing risk for heart attack and stroke outweighs the small increase in risk for diabetes. A few pounds of weight loss can fully counteract the effect of a statin on diabetes risk.
      • 6.
        If you feel that you have experienced a side effect (usually muscle aches) while taking a statin, the decision of whether to continue taking the statin is your decision to make, guided by the best advice that your health care provider can give. Before stopping a statin due to possible side effects, it is generally recommended that you speak to your health care provider first. Often it can be difficult to decide whether the symptoms a person experiences are truly caused by the statin. Because of the good safety record of statins, it is reasonable to ask how bothersome the symptoms are, and continue with statin treatment if you feel that the symptoms are minor, readily tolerated, and not so bothersome that your ability to exercise is limited.
      • 7.
        Experience has shown that most people who experience intolerance to a statin will still be able to take a different statin or perhaps the same statin at a lower dose. Although higher doses of statins have the best record for preventing heart attacks and strokes, lower doses (for example, one quarter as much) can often provide benefit by lowering LDL-C and possibly reducing your chances of heart attacks and strokes. Given how beneficial statins are in the prevention of heart attack and stroke, a health care provider may often try different statin drugs at different doses to help find one that you can tolerate. Most patients who have symptoms on 1 statin can usually tolerate a different statin or the same statin at a lower dose.
      • 8.
        If you cannot take a statin at any dose, or if you do not get enough cholesterol lowering while taking a statin (perhaps because the dose has been reduced), your provider may recommend or prescribe 1 of several alternative drugs for lowering cholesterol. There is some evidence that alternative cholesterol medications reduce risk for heart attacks and strokes, although the evidence is not as conclusive as it is for statins.
      • 9.
        Apart from cholesterol-lowering medication, diet and lifestyle changes can reduce heart attack and stroke risk. A person can lower their LDL-C by reducing trans and saturated fat in the diet, by adding plant sterol esters or stanol esters (the margarines Promise Activ and Benecol are known to lower LDL-C), and by increasing consumption of soluble or viscous fiber such as that found in beans, oat or rice bran, and psyllium powder (Metamucil and other brands). However, it is very difficult to get as much LDL-C lowering as a statin provides, by diet and lifestyle changes alone.

      Recommendations for research on statin intolerance

      • 1.
        The frequency of statin intolerance will be best determined from the combined results of observational studies and prospective randomized clinical trials.
      • 2.
        Development of a validated index of statin muscle intolerance is an important early goal for research.
      • 3.
        The following design elements for clinical trials should be strongly considered: (a) statin tolerance as the primary end point; (b) randomized, blinded comparison of statin vs placebo medication; and (c) recruitment of patients with a personal history of statin intolerance.
      • 4.
        Alternative strategies for achieving LDL-C–lowering goals should be investigated using varying combinations of statin and nonstatin drugs.
      • 5.
        In addition to the foregoing, research on the causes, impact, and possible amelioration of statin intolerance should receive increased attention. Properly designed randomized trials should assess whether supplementation with vitamin D, coenzyme Q10, and other potential therapies may improve statin tolerability.

      Financial disclosures

      The following authors disclose that they have modest relationships with industry that might pose a potential conflict of interest(s). Dr. Guyton has received research grants from Merck, Abbott, Genzyme, Sanofi, Regeneron, GSK, Amarin, and Amgen and consulting fees from Merck, Regeneron, and ARMO Biosciences. Dr. Harold Bays has served as a consultant and/or speaker to Amarin, Amgen, Astra Zeneca, Bristol Meyers Squibb, Catabasis, Daiichi Sankyo, Eisai, Isis, Merck, Novartis, VIVUS, WPU, and his research site has received research grants from Alere, Amarin, Amgen, Ardea, Astra Zeneca, Boehringer Ingelheim, Bristol-Myers Squibb, California Raisin Board, Catabasis, Eisai, Elcelyx, Eli Lilly, Esperion, Essentialis, Forest, Gilead, Given, GlaxoSmithKline, High Point Pharmaceuticals LLC, Hoffman LaRoche, Home Access, Janssen, Merck, Metabolex, Micropharma Limited, Necktar, Novartis, Novo Nordisk, Omthera, Orexigen, Pfizer, Pronova, Regeneron, Stratum Nutrition, Takeda, TIMI, Transtech Pharma, Trygg, VIVUS, WPU, and Xoma. Dr. Scott Grundy discloses that he has received an honorarium as a consultant to Sanofi. Dr. Jacobson is a consultant for Amarin, Amgen, Astra Zeneca, Merck, Sanofi, and Regeneron.

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