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Editorial
November 15, 2016

Interpretation and Use of Another Statin Guideline

Author Affiliations
  • 1Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
  • 2Senior Editor, JAMA
  • 3Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
  • 4Editor, JAMA Cardiology
JAMA. 2016;316(19):1977-1979. doi:10.1001/jama.2016.15087

The US Preventive Services Task Force (USPSTF) guideline on statin use for the primary prevention of cardiovascular disease (CVD) in adults and the evidence report that supports the USPSTF statement1,2 published in this issue of JAMA add to 4 other major guidelines on the use of statins published since 2013.36 It is self-evident that if they were identical, there would be no justification for more than a single guideline. Therefore, it is important to understand the differences and determine how to provide clinical care and guidance for patients that accounts for the differences. Despite numerous randomized clinical trials (RCTs), important evidence gaps persist, resulting in disparate recommendations among guideline writing groups.

The USPSTF made 6 recommendations. First, initiate low- to moderate-dose statin treatment for “adults aged 40 to 75 years without a history of CVD who have 1 or more CVD risk factors and a calculated 10-year CVD event risk of 10% or greater (grade B recommendation).” For the purposes of the recommendation, the CVD risk factors were dyslipidemia, diabetes, hypertension, or smoking. In making this recommendation, the task force noted that participants in RCTs “generally” had 1 or more CVD risk factors and were not recruited based on any particular calculated risk score. The statin recommendation is a change for the USPSTF, since they previously had not recommended widespread statin use for primary prevention of CVD. Second, determine the 10-year CVD risk using the Pooled Cohort Equations7 developed for use with the American College of Cardiology/American Heart Association (ACC/AHA) lipid treatment guideline.4

Third, “selectively offer low- to moderate-dose statins to adults aged 40 to 75 years without a history of CVD who have 1 or more CVD risk factors and a calculated 10-year CVD event risk of 7.5% to 10% (C recommendation).” To do so, clinicians are encouraged to use the Pooled Cohort Equations along with individualized decision making by considering the known potential benefits and harms of statins. Fourth, “current evidence is insufficient to assess the balance of benefits and harms of initiating statin use in adults 76 years and older” without a history of heart attack or stroke (I statement). This statement is based on the relative paucity, but not complete lack, of trial evidence for initiating statins among people 76 years and older.

Fifth, there is no direct evidence from RCTs to guide the choice of a specific CVD risk threshold for initiating statins. However, the available trial evidence for statin use among adults at increased risk of CVD, but without a history of CVD events, generally demonstrates consistent benefits across different clinical and demographic subgroups (even among adults without marked hypercholesterolemia).8 As such, the likelihood that patients will benefit from statin treatment is directly associated with their absolute baseline risk of experiencing a CVD event. Sixth, recommendations do not pertain to adults with very high CVD risk, such as those with familial hypercholesterolemia or a low-density lipoprotein cholesterol (LDL-C) concentration greater than 190 mg/dL, because they were excluded from primary prevention trials. Per the USPSTF statement, these persons should be screened and treated in accordance with clinical judgment for the treatment of dyslipidemia.

How do the USPSTF recommendations differ from the other 4 statin guidelines, and how do those guidelines differ from each other? The ACC/AHA guideline4 recommended use of moderate- to high-dose statins for most asymptomatic adults aged 40 to 75 years without a history of CVD who have an LDL-C concentration of 190 mg/dL or greater, diabetes, or an estimated 10-year CVD event risk of 7.5% or greater, as calculated with the Pooled Cohort Equations risk calculator. Shared decision making was emphasized before initiating moderate- to high-dose statin treatment. Although based on a review of trial evidence concerning RCT enrollment criteria, the recommendation for use of a moderate- to high-dose statin was based on an extrapolation of the benefits of lowering LDL-C concentration in the absence of specific target LDL-C goals in the RCTs. This topic was recently reviewed in a meta-regression analysis in JAMA9 suggesting that lower LDL-C concentration is associated with lower relative risk of major vascular events. The Canadian Cardiovascular Society3 recommended statin therapy combined with health behavior modification in men 40 years and older and women 50 years and older with a 10-year CVD event risk less than 10% based on the Framingham risk score10 but who have an LDL-C level of 5 mmol/L (193 mg/dL) or genetic hypercholesterolemia; adults of any age with CVD risk factors with a 20% or greater 10-year CVD event risk; and adults with a 10% to 20% CVD event risk who have an LDL-C level of 135 to 190 mg/dL. The treatment strategy is treat-to-target (eg, ≥50% reduction in LDL-C level) rather than by therapy dose. The UK National Institute for Health and Care Excellence5 recommended statin therapy (specifically, atorvastatin [20 mg]) for the primary prevention of CVD events in adults 40 years and older with a 10% or greater 10-year CVD event risk, as estimated by the QRISK2 assessment tool.11 Before offering statin therapy, clinicians were advised to discuss the benefits of lifestyle modification and optimize the management of all other modifiable CVD risk factors.

The European Society of Cardiology and European Atherosclerosis Society 2016 guideline on assessment and management of dyslipidemias6 takes an approach that is very different from the others and is somewhat complex. In brief, they made 7 recommendations. First, evaluate the total CVD risk using the European SCORE tool.12 Second, involve the patient with decisions on CVD risk management, similar to the other guidelines. At this point, the approach differs substantially from the other guidelines. Third, identify the LDL-C target for the patient’s risk level, with varying targets depending on the patient’s risk. Fourth, calculate the percent reduction of LDL-C level required to achieve the LDL-C goal. Fifth, choose a statin that, on average, can provide the target reduction. Sixth, since the response to statin treatment is variable, up-titrate drug doses to reach targets. And seventh, if the statin treatment alone cannot achieve the goal, consider drug combinations.

There is considerable agreement among the 5 guidelines but also some important disagreement, primarily when the data are limited. There is agreement on strong evidence for statin effectiveness and broad treatment indications, especially among the highest-risk segments of the adult population, including individuals with familial hypercholesterolemia or diabetes and patients with established atherosclerotic CVD. There is also consistent agreement that statins are generally safe, especially among individuals younger than 76 years. This is supported by a vast body of evidence.8 There is uncertainty and hesitation in all the guidelines regarding the benefits and risks of statins among older people, for whom evidence from RCTs is limited. There is lack of agreement on specific LDL-C targets of therapy because only observational evidence is available on this point. None of the statin RCTs has specifically compared one LDL-C target with another, although compelling observational evidence suggests benefit of LDL-C lowering across a range of achieved LDL-C concentrations.9 Thus, the issue of specific LDL-C targets is unresolved. There is also disagreement on specific treatment initiation thresholds, with the ACC/AHA guideline recommending the lowest threshold. Cost-effectiveness analyses have suggested that even the threshold selected by the ACC/AHA may be too high.13 In the absence of specific trials on the exact threshold, disagreement is inevitable. Despite rather substantial trial evidence on the use of statins for primary prevention of CVD, uncertainties remain, and all 5 of the guidelines uniformly advise that clinical judgment along with thoughtful patient-clinician discussions is indicated, regardless of level of patient risk. All guidelines also emphasize the importance of lifestyle interventions to reduce risk in all patients, regardless of lipid-lowering drug use.

There are several important take-home messages. First, it is critically important to ensure at least some intensity of statin use by higher-risk patients and patients similar to those studied in the RCTs. A recent article by Pavlovic et al14 emphasized that many patients for whom the benefits are undeniable for evidence-based use of statins are not receiving any statin at all. Every patient at age 40 years or older should be considered for possible statin therapy. Second, in the absence of clear agreement on risk thresholds, several of the guidelines suggested the possibility that additional testing, beyond risk factors alone, may assist in treatment decisions. The most helpful test in this regard appears to be coronary artery calcium scoring, and its selective use is recommended in the setting of uncertainty following a patient-physician discussion based on available evidence.15,16 Third, all of the guidelines are correct in suggesting that additional trial evidence is needed for older adults, but this will be years in the future. Until such trial evidence is available, it is reasonable to extrapolate data from younger patients to include otherwise healthy individuals older than 75 years, and it is not necessary to stop statin therapy when a 75-year-old turns 76. Last, and perhaps most important, clinical judgment and patient input are critical components of the decision process,17 especially for older patients and those at lower risk.

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Article Information

Corresponding Author: Philip Greenland, MD, Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, 680 N Lake Shore Dr, 14th Floor, Chicago, IL 60611 (p-greenland@northwestern.edu).

Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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