Author + information
- Received November 5, 2017
- Revision received December 15, 2017
- Accepted December 15, 2017
- Published online February 12, 2018.
- aDivision of Cardiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
- bAmerican College of Cardiology, Washington, DC
- ↵∗Address for correspondence:
Dr. Neil J. Stone, Division of Cardiology, Northwestern University Feinberg School of Medicine, 676 North St. Clair Street, Suite 600, Chicago, Illinois 60611.
Lipid treatment guidelines have continued to evolve as new evidence emerges. We sought to review similarities and differences of 5 lipid treatment guidelines from the American College of Cardiology/American Heart Association, Canadian Cardiovascular Society, European Society for Cardiology/European Atherosclerosis Society, U.S. Preventive Services Task Force, and U.S. Veterans Affairs/Department of Defense. All guidelines utilize rigorous evidentiary review, highlight statin therapy for primary and secondary prevention of atherosclerotic cardiovascular disease, and emphasize a clinician-patient risk discussion. However, there are differences in statin intensities, use of risk estimators, treatment of specific patient subgroups, and consideration of safety concerns. Clinicians should understand these similarities and differences in current and future guideline recommendations when considering if and how to treat their patients with statin therapy.
With lipid guidelines, as with history, “nothing stands still” (1). Through completion of large-scale randomized controlled trials, high-quality clinical evidence emerges that drives changes in major guidelines. We sought to clarify similarities and differences to improve clinicians’ critical sense of lipid guidelines as they evolve.
We considered 5 guidelines on the treatment of hypercholesterolemia recently published by high-profile cardiovascular societies: 2014 American College of Cardiology (ACC)/American Heart Association (AHA) Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults (2); 2016 Canadian Cardiovascular Society (CCS) Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular Disease in the Adult (3); 2016 European Society for Cardiology (ESC)/European Atherosclerosis Society (EAS) Guidelines for the Management of Dyslipidaemias (4); 2016 U.S. Preventive Services Task Force (USPSTF) report, Statin Use for the Primary Prevention of Cardiovascular Disease in Adults (5,6); and 2014 U.S. Department of Veteran Affairs–U.S. Department of Defense (VA-DoD) Clinical Practice Guideline for the Management of Dyslipidemia for Cardiovascular Risk Reduction (7) (Central Illustration).
Guidelines Evidentiary Processes
The guidelines were drafted and verified by panels comprising experts in the field. The ACC/AHA and VA-DoD utilized 2 distinct panels for evidentiary review and guideline composition, whereas the CCS, ESC/EAS, and USPSTF employed single working groups to review evidence and draft the guidelines. Committees used a strict evidentiary review process. For example, the ACC/AHA considered only randomized control trials (RCTs), systematic reviews of randomized control trials, and meta-analyses that were rated fair to good by an independent contractor. Poorly rated studies were excluded. The USPSTF and VA-DoD described the use of RCTs and systematic reviews of RCTs, although without discussion of explicitly excluding poorly rated studies. Although the CCS and ESC/EAS used a strict analysis of the published data and cited references for recommendations, they did not state limitations on the types of papers used (Table 1).
The purview of all guidelines except for the USPSTF (primary prevention only) encompasses primary and secondary atherosclerotic cardiovascular disease (ASCVD) prevention. Each guideline describes varying certainty for each recommendation, as well as the strength of evidence to support it. For example, the ACC/AHA and ESC/EAS writers provide Classes of Recommendation (I, IIa, IIb, and III) and Levels of Evidence (A to C). VA-DoD uses “high,” “moderate,” “low,” and “very low” to describe quality of evidence, and recommendations are either “strong” or “weak” and “for” or “against.”
The ethos of each writing committee is essentially similar, with expert and rigorous review, inclusion of high-quality published data, and consensus generation in drafting the recommendations; however, there are varying degrees of transparency disclosed in each guideline. This does not necessarily affect the validity of each guideline, but can affect the level of debate surrounding the more contentious recommendations.
Risk Estimators and Primary Prevention
Each guideline makes recommendations on statin therapy for primary prevention using various estimators for 10-year risk of ASCVD events. The ACC/AHA and USPSTF recommend the use of the ACC/AHA Pooled Cohort Risk Equations, whereas the CCS recommends use of the Framingham Risk Score (FRS), and VA-DoD suggests the use of either mechanism. The ESC/EAS recommend use of the Systemic Coronary Risk Evaluation (SCORE) estimator.
Risk estimators are derived from large studies in the United States or Europe. All include age, sex, total cholesterol, high-density lipoprotein cholesterol (HDL-C), and systolic blood pressure as predictors. However, ethnicity, treatment for hypertension, diabetes, and smoking status are only included in some; thus, patient risk may vary with different estimators (Table 2).
Outcomes are different between risk estimators. Outcome for the FRS is the most inclusive, predicting 10-year risk of coronary heart disease, cerebrovascular events, peripheral artery disease, or heart failure. The ACC/AHA Pooled Cohort Risk Equations are restrictive, predicting 10-year risk for first hard ASCVD event, defined as coronary heart disease death, nonfatal myocardial infarction (MI), or stroke. The SCORE estimator is most specific, predicting 10-year risk of first fatal atherosclerotic event, including MI, stroke, other occlusive arterial disease, or sudden cardiac death. These differences in outcome measures are important when considering differences in treatment thresholds between the guidelines.
Thresholds for which treatment is recommended range between 5% and 20% 10-year risk of ASCVD. The lowest threshold is from the ESC/EAS, which recommends statin treatment for patients with 5% to 10% 10-year ASCVD risk and LDL-C ≥100 mg/dl. ESC/EAS recommends use of the SCORE risk estimator, which has the strictest outcome by predicting risk of only fatal events. The highest threshold for treatment is ≥20% 10-year ASCVD risk using the FRS estimator, which predicts risk of the broadest outcomes. The ACC/AHA, USPSTF, and VA-DoD recommend treatment at thresholds of ≥7.5%, ≥10%, and ≥12% 10-year risk of ASCVD respectively, using the ACC/AHA Pooled Cohort Risk Equations. Of note, all of the guidelines recommend treatment for patients with LDL-C ≥190 mg/dl.
Despite the wide range in treatment thresholds between the guidelines, the number of patients for which statin treatment is recommend or considered is likely similar given the differences in outcomes in the risk estimators. Of adults age 40 to 65 years, a comparative analysis estimated the ACC/AHA and ESC/EAS guidelines respectively recommend statin treatment in 43.8% versus 39.1% in the United States and 49.9% versus 47.6% in Poland (8). In other words, a 7.5% risk derived from one risk estimator may be equivalent to a 10% risk from another, depending on outcomes predicted by each. This suggests that individuals for whom statin therapy is recommended or should be considered for primary prevention may ultimately not differ greatly amongst guidelines, and highlights the importance of the clinical-patient risk discussion.
The guidelines highlight the importance of lifestyle prior to and in conjunction with pharmacotherapy for reducing the risk of ASCVD. The components of lifestyle emphasized include heart-healthy diets, reducing excessive weight, avoidance of tobacco, and physical activity.
Statins are the recommended initial pharmacotherapy, but differ between guidelines in intensity or dose of therapy. The CCS focuses on a targeted reduction in LDL-C level without discussion of statin intensity or dose. Similarly, the ESC/EAS uses absolute LDL-C levels as a treat-to-target goal. The ACC/AHA, USPSTF, and VA-DoD recommend statin intensity or dose based on clinical profiles. The ACC/AHA employs statin intensity in LDL-C reduction, which is delineated into high-, moderate-, and low-intensity categories targeting a reduction in LDL-C ≥50%, 30% to 50%, and <30%, respectively. The USPSTF and VA-DoD suggest dosage of statin for LDL-C reduction. In both guidelines, high-, moderate-, and low-dose statins reflect the same categorization as high-, moderate-, and low-intensity statins as the ACC/AHA. We believe “intensity” is the most appropriate terminology for guidelines, because similar doses of different statins may have different intensities as defined as level of LDL-C reduction.
The guidelines suggest considering nonstatin therapies for patients with statin intolerance or inadequate therapeutic response on statin therapy. However, lesser quality of evidence leads to relatively weaker recommendations at this time.
The ACC/AHA, USPSTF, and VA-DoD recommend different intensities or dosages of statins for primary prevention based on 10-year risk thresholds. The ACC/AHA recommends using a moderate- or high-intensity statin (in patients with ≥7.5% 10-year ASCVD risk). The USPSTF and VA-DoD recommend either a low- or moderate-dose statin without use of a high-dose statin in any cohort. As discussed, the CCS and ESC/EAS use treatment goals to determine selection and dosing of statins. Importantly, all guidelines recognize the importance of shared decision-making and emphasize a clinician-patient risk discussion.
The ACC/AHA and VA-DoD recommend varying intensities or doses of statins for secondary prevention in patients with ASCVD. The ACC/AHA recommends high-intensity statins for patients age ≤75 years without contraindications and moderate-intensity statins for the other groups. The VA-DoD recommends a moderate-dose statin for most patients with ASCVD and a high-dose statin for select patients deemed to be at high risk for future events. The CCS and ESC/EAS again use treatment goals to determine statin selection and dosing.
All guidelines suggest statin use in the elderly (defined as age >75 years or life expectancy <5 years) as a point of uncertainty. The ACC/AHA recommends continuing a statin if already tolerating, recommends not starting one for primary prevention, and recommends initiating a moderate-intensity statin for secondary prevention. The ESC/EAS considers initiating a statin for primary prevention if ASCVD risk is particularly high, although it recommends a lower starting dose of statin and gradual titration to reach the target, given altered pharmacokinetics in the elderly. The CCS recommends a physician-patient discussion in high-risk patients, and the VA-DoD employs a decision based on comorbidities, quality of life, patient preferences, values, and culture. The USPSTF indicates that there is insufficient evidence to recommend statin initiation in the elderly.
End-stage renal disease
The ACC/AHA makes no specific recommendations for or against the initiation or discontinuation of statins in end-stage renal disease patients on maintenance hemodialysis. The VA-DoD leaves it as a treatment decision based on patient comorbidities, quality of life, preferences, values, and culture. The CCS explicitly instructs not to initiate therapy in dialysis-dependent patients, but to continue statin therapy in those already receiving it at the time of dialysis initiation.
The ACC/AHA and ESC/EAS mention solid organ transplantation and patients with human immunodeficiency virus, recommending caution with drug–drug interactions (particularly cyclosporine) and potential initiation at lower doses with careful titration. The ACC/AHA and ESC/EAS suggest clinical judgement in statin initiation with rheumatologic and inflammatory diseases given insufficient evidence. ESC/EAS highlights patients with psychiatric disorders as a barrier to medication compliance.
The various guidelines treat these special groups with uncertainty in statin usage because of the lack of rigorous data that show significant and unequivocal benefit or harm.
Often overlooked, safety and monitoring are critical for appropriate statin use (Table 3). The ACC/AHA and ESC/EAS both recommend routine monitoring. They recommend caution with appropriate dose reductions in patients with impaired renal or hepatic function, patients with unexplained alanine transaminase elevation ≥3× the upper limit of normal, elderly patients, patients taking concomitant drugs that alter statin metabolism, those with a history of previous stain intolerance or muscle disorders, and patients of Asian ancestry.
We undertook a comparative analysis of 5 major lipid treatment guidelines. We found a high degree of consensus in recommendations. All utilize a rigorous evidentiary process emphasizing statins for primary/secondary prevention. Moreover, all recommend joint decision-making with a clinician-patient discussion. However, there are differences. Recommendations on statin intensity, on patients with particular comorbidities, and addressing safety concerns vary among the guidelines. Furthermore, the utilization of differing risk estimators requires an a priori understanding of compounding comorbidities and their influence on pre-test probability of ASCVD. The incorporation of new high-quality data could help resolve some of these differences. Clinicians can look forward to improved resolution of areas where treatment decisions diverge as evidence-based recommendations evolve. Nothing stands still.
Dr. Stone served as lead author of the 2013 ACC/AHA cholesterol guidelines.
The authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Tibrewala and Jivan contributed equally to this work and are joint first authors.
- Abbreviations and Acronyms
- American College of Cardiology
- American Heart Association
- atherosclerotic cardiovascular disease
- Canadian Cardiovascular Society
- coronary heart disease
- European Atherosclerosis Society
- European Society of Cardiology
- Framingham Risk Score
- myocardial infarction
- Systemic Coronary Risk Evaluation
- U.S. Preventive Services Task Force
- Veterans’ Affairs–Department of Defense
- Received November 5, 2017.
- Revision received December 15, 2017.
- Accepted December 15, 2017.
- 2018 American College of Cardiology Foundation
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