Author + information
- Received December 3, 2013
- Revision received January 28, 2014
- Accepted February 25, 2014
- Published online June 24, 2014.
- Seth S. Martin, MD,
- Thura T. Abd, MD, MPH,
- Steven R. Jones, MD,
- Erin D. Michos, MD, MHS,
- Roger S. Blumenthal, MD and
- Michael J. Blaha, MD, MPH∗ ()
- ↵∗Reprint requests and correspondence:
Dr. Michael J. Blaha, Blalock 524C–Johns Hopkins Hospital, 1800 Orleans Street, Baltimore, Maryland 21287.
Five years after convening the expert panel, the 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults was released. The American College of Cardiology and American Heart Association issued the guideline on the basis of a systematic review of cholesterol treatment trials performed by the National Heart, Lung, and Blood Institute. This report critically appraises the guideline and provides our view of what was done well and what could be done better. In particular, we propose that the guideline succeeds in prioritizing statin therapy, expanding the focus to atherosclerotic cardiovascular disease (including stroke), and emphasizing absolute cardiovascular risk to determine eligibility for statin therapy. We contend that the guideline could be enhanced by refining the use of lipid goals rather than removing them, enhancing guidance on evaluation of cholesterol, and broadening the concept of age underpinning risk-based decision making to include vascular and physiological age. We further suggest that the next guideline panel could comprehensively review current best evidence, build on existing guidelines, and cultivate broader national and international consensus. Overall, we aim to continue discussions about the important contributions and shortfalls of the guideline and create momentum for effective implementation and timely updates.
- cardiovascular disease
- coronary heart disease
- myocardial infarction
Five years after it was commissioned, the document previously known as “ATP IV” was issued on November 12, 2013, under a revised name, “2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults” (henceforth abbreviated as “CTG” for “Cholesterol Treatment Guideline”) (1). The American College of Cardiology and American Heart Association (ACC/AHA) issued the CTG on the basis of a systematic review of cholesterol treatment trials. This report critically appraises the CTG and provides our view of what was done well and what could be done better in future iterations.
What Was Done Well
Prioritizing statin therapy
The CTG succeeds in prioritizing statin therapy, which is in line with recommendations from our group (2) and others (3). Over the decade since the original publication of the Adult Treatment Panel (ATP) III guideline, the Cholesterol Treatment Trialists' Collaboration has further expanded the extraordinary wealth of information on statin therapy (4,5). This class of medications is 1 of the best validated to reduce the morbidity and mortality from atherosclerotic cardiovascular disease (ASCVD) and has an excellent safety profile (1,2,4). Moreover, generic options for moderate- and high-intensity statin formulations are now available. We anticipate that prioritizing statins will lead to much less use of nonstatin therapy in patients not yet on maximally tolerated statin therapy.
Expanding the focus to ASCVD
Cerebrovascular disease and coronary heart disease (CHD) share risk factors and the underlying disease process of atherosclerosis. Lipid-lowering interventions reduce clinical events related to ASCVD, not only CHD. Therefore, addressing the broader disease construct is justified and more efficient.
There are complexities to this expanded paradigm, not limited to the fact that 1 of multiple underlying pathophysiological mechanisms can cause a stroke, and the distinction can be challenging to adjudicate. Although we must carefully scrutinize and understand how to manage such complexities, on balance, expanding the framework from CHD to ASCVD is an important and welcome change (6).
Emphasizing absolute cardiovascular risk
The CTG emphasizes absolute risk in the allocation of statin therapy. The CTG recommends moderate- to high-intensity statin therapy in groups with high absolute risk, including patients with clinical ASCVD, those 40 to 75 years of age with diabetes mellitus, and those with low-density lipoprotein cholesterol (LDL-C) levels ≥190 mg/dl. The CTG prioritizes these 3 groups on the basis of prevailing evidence from randomized controlled trials.
For those not in one of these groups, if the patient has an LDL-C level of 70 to 189 mg/dl and is 40 to 75 years of age, then the CTG advises calculation of 10-year risk of ASCVD on the basis of traditional risk factors using new sex- and race-stratified pooled cohort equations developed by the ACC/AHA Risk Assessment Working Group (7). Concern about overestimation of risk by these equations is being debated (8,9), and further validation studies are necessary. Nevertheless, we appreciate the intention to address absolute risk in primary prevention. In the CTG, the risk calculator does not mandate drug prescription but rather serves as a starting point for a discussion about risk between the patient and the clinician. This discussion may lead to additional testing to refine the estimate of absolute risk. The CTG identifies the intermediate-risk group as people with a 5% to 7.5% 10-year risk of ASCVD and recommends a discussion about risk in people with ≥7.5% risk.
What Could Be Done Better
Refine the use of lipid goals rather than remove them
There are potential downsides to lipid goals. They could lead to overuse of nonstatin agents and combination regimens instead of maximizing statin therapy. This could increase the propensity for adverse effects, which could be problematic specifically in primary prevention patients with less certain absolute ASCVD risk and, therefore, less certain benefits. Moreover, lipid goals could conceivably result in withholding of efficacious treatment in a person with an LDL-C level <100 mg/dl. Prior guidelines may not have recommended intensive statin therapy, or a statin at all, in higher-risk patients with low or average off-treatment levels of LDL-C (100 to 130 mg/dl), yet this group has a similar proportional risk reduction from lowering of LDL-C levels (4). Therefore, applying a lipid goal at baseline could lead to underuse of statins in higher-risk patients.
We could address these issues without abandoning lipid goals. To do so, we could refocus the use of lipid goals as an option to guide residual risk discussions on follow-up among those with a clearly established risk of ASCVD while making it explicitly clear that maximizing the statin dose is the first priority. Even in secondary prevention trial populations carefully selected to adhere to high-intensity statin therapy, many patients did not attain optimal levels of atherogenic cholesterol. In statin-treated patients, LDL-C, non–high-density lipoprotein cholesterol (non–HDL-C), and apolipoprotein B are markers of residual risk (10). Considering LDL-C and non–HDL-C on follow-up in relation to explicit goals, as was done in ATP III, could alert the patient and provider that levels are still suboptimal. This does not need to trigger automatic addition of drug therapy. Rather, it could prompt a discussion of residual risk and options for further intensification of lifestyle improvements and add-on drug therapy, particularly in the setting of an elevated triglyceride level and a low HDL-C level. Because the anticipated net benefits of further lipid lowering are clearest in those with the most clearly established risk, we believe that lipid goals are best justified in high-risk secondary prevention.
It is true that there has not been a definitive randomized clinical trial of the addition of a second lipid-lowering agent in secondary prevention patients with residually elevated atherogenic cholesterol levels. There are many clinical situations, including in the management of hypertension, in which there are no randomized trials of ASCVD outcomes with the addition of drug A to drug B or the addition of drug C to drugs A and B. However, we could learn from landmark strategy trials such as the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial, in which statins and nonstatins were titrated to an LDL-C goal of 60 to 85 mg/dl. The central test of the trial was optimal medical therapy with or without percutaneous coronary intervention, and it forms part of the foundation for management of patients with stable CHD. A COURAGE-like strategy to medical management includes an LDL-C goal.
As previously reviewed (11,12), complementary lines of evidence support the low LDL-C goal used in the COURAGE trial (or similar goals such as <80 or <70 mg/dl). First, LDL-C levels in this range appear to be evolutionarily or biologically normal. Second, those with genetically determined low LDL-C levels are strongly protected from ASCVD. Third, trials and observational studies have consistently shown a log-linear association of lower LDL-C level with lower risk of ASCVD. Fourth, populations treated to low LDL-C levels in trials were more likely to have stabilization or regression of atherosclerosis. Fifth, the Cholesterol Treatment Trialists' Collaboration has shown that the benefit of statin therapy is tied not only to absolute ASCVD risk but also to the absolute lowering of LDL-C levels, with each 39-mg/dl (1-mmol/l) reduction in LDL-C level decreasing the incidence of ASCVD by approximately one-fifth. Finally, subgroups of patients attaining the lowest LDL-C levels in these trials had the best outcomes without any significant increases in major adverse effects. Therefore, like COURAGE, ATP III, and guidelines in Europe and Canada, we could use this information to manage residually elevated LDL-C levels.
Because LDL-C will not capture triglyceride-rich remnant lipoproteins, we could also consider non–HDL-C or apolipoprotein B. A previous meta-analysis of statin and nonstatin lipid-lowering drugs used as monotherapy found a ∼1:1 percent lowering between non–HDL-C level and risk of CHD (13). Pre-specified subgroup analyses of trial participants with high triglyceride and low HDL-C levels (markers for remnants) are informative on the potential benefit of adding a fibrate (14) or niacin (14,15) to statin therapy. These studies have shown a consistent trend for benefit.
Therefore, “treating risk” and “treating lipids” are not mutually exclusive and are actually complementary. Absolute risk places the lipids in context and can guide discussions weighing potential benefits and harms. However, lipid goals provide a marker for adequacy of lipid lowering. They not only help ensure adherence to lifestyle improvements and statin therapy but also help guide therapy in high-risk patients in whom these treatments are exhausted.
Enhance guidance on evaluation of cholesterol
The CTG does not include “evaluation” in its title, as it was in ATP III. However, new information has become available on the evaluation of cholesterol since ATP III. Although the risk assessment guideline examines this information to some extent, evaluation of cholesterol is not purely an issue of risk assessment.
For example, at baseline, the CTG recommends treatment if the LDL-C level is ≥70 mg/dl but not if it is <70 mg/dl. Therefore, accurate measurement in the individual patient is critical to management. Expanding prior evidence, we have shown that of patients who have a Friedewald-estimated LDL-C level <70 mg/dl, 23% have a directly measured LDL-C level ≥70 mg/dl (39% if the triglyceride level is 150 to 199 mg/dl and 59% if the triglyceride level is 200 to 399 mg/dl) (16). If externally validated, a novel method for estimation of LDL-C levels could resolve much of the underestimation of LDL-C levels by accounting for variation in the relationship of triglycerides to very-low-density lipoprotein cholesterol (17).
The next guideline could translate new knowledge on cholesterol evaluation. It could take a leadership role in guiding clinicians on not only LDL-C but also non–HDL-C, apolipoprotein B, and LDL particle concentration. Along with the science, there are historical, financial, and logistical considerations, and an expert panel is well suited to weigh these factors.
Broaden the concept of age
The CTG emphasizes chronological age in treatment decisions. For example, the CTG explicitly recommends statin therapy only in patients who are 40 to 75 years of age. This same age range also determines who undergoes 10-year ASCVD risk calculation to guide treatment decisions. Age dominates the risk calculator, with the 7.5% risk threshold exceeded by nearly all men in their mid to late 60s and nearly all women in their 70s despite an optimal risk factor profile.
However, people age differently. We submit that a broader construct of age may enhance risk discussions and treatment decisions. “Heart age” and “vascular age” could help patients better understand how their risk compares with their chronological age. Moreover, the concepts of “health age” or “physiological age” could be used to assess our patients' noncardiovascular comorbidities or competing risks, which could affect the net benefits from intervention. If the patient is free of competing risks, then we would suggest that the CTG could be less cautious in those older than 75 years of age. The meta-analysis by the Cholesterol Treatment Trialists' Collaboration included 1,872 events in subjects older than 75 years of age, and there was no evidence of heterogeneity of treatment effect by age (4). A meta-analysis focused on elderly patients without ASCVD at baseline, involving 24,674 subjects with a mean age of 73.0 ± 2.9 years and 3.5 ± 1.5 years of follow-up, found a significant reduction in ASCVD outcomes with statin therapy (18).
We would also like to prevent significant accumulation of atherosclerosis earlier in life. A risk score dominated by chronological age favors late treatment. Once atherosclerosis progresses to an advanced stage, there may be an associated degree of unmodifiable risk. Although speculative, preventing significant progression of atherosclerosis in the first place may help avoid at least part of this residual risk. It is striking that the relative risk reduction associated with a genetically low LDL-C level is larger than that with later-stage drug therapy (19).
We submit the following for debate: if you are stuck on a deserted island, have significant subclinical atherosclerosis or heterozygous familial hyperlipidemia with an LDL-C level of 189 mg/dl, and have only enough statin to take for 20 years, would you take it from 30 to 50 years of age or 50 to 70 years of age?
Comprehensively review current best evidence, build on existing guidelines, and refine the CTG during implementation
Evidence-based medicine is “the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients” (20). Aimed at supporting evidence-based medicine, the CTG conducted a systematic search of randomized controlled trials through December 2009, and was also allowed to consider trials through July 2013. The phrase “no evidence” could be a dangerous claim (21), especially when all current best evidence has not been considered.
A search on PubMed for “cholesterol” on the day the CTG was released yielded 219,290 published scientific reports. In answering “Critical Question 1” about lipid goals, the CTG screened 2,224 titles and abstracts, that is, ∼1% of the published literature.
To construct a comprehensive guideline, the writing group did not necessarily need to re-review >200,000 published scientific reports. The ATP III critically appraised and synthesized the relevant literature through 2004 (22). In addition, specialty societies such as the National Lipid Association (NLA) (23) and the American Association of Clinical Endocrinologists (AACE) (24) have recently issued recommendations for the management of cholesterol disorders.
The NLA and the AACE each provided input to the National Heart, Lung, and Blood Institute and ACC/AHA during the development of the CTG but ultimately did not endorse the document. The reasons why the NLA and the AACE each did not endorse the CTG were explained in public statements (25,26). Each group cited the highly restrictive consideration of evidence, removal of lipid targets, too little guidance on nonstatin options, and insufficient consideration of special populations of patients.
Outside of the United States, while the United Kingdom just released a provisional guideline for stakeholder comment (27), experts in Europe (28) and Canada (29,30) have already completed updated guidelines. The International Atherosclerosis Society has also released a position paper on the management of dyslipidemia (31). These international efforts address many of the concerns noted by the NLA and AACE. In moving forward, we propose building on these prior efforts. Ideally, the ACC/AHA could collaborate with professional societies around the globe to build broader consensus and produce an international consensus guideline on cholesterol treatment.
It is easy to imagine the potential benefits to guideline implementation from pooling resources and broadening consensus. The critical rollout phase of the CTG could leverage the influence of professional societies and engage the expertise of transdisciplinary teams inclusive of implementation scientists to help overcome barriers to guideline adherence at the bedside. For example, guideline documents such as the CTG can be long, tedious, and very repetitive. Although an important scholarly exercise, this form of information is far from user-friendly. Instead, implementation scientists recommend a prioritized checklist of unambiguous behaviors organized in time and space, citing the level of evidence (32). A checklist could be printed and posted in the clinic, made available online, or included in a smartphone app.
Implementation scientists have identified a number of other barriers to guideline adherence, including lack of awareness or ability, clinical inertia, disagreement with recommendations, or ambiguity of recommendations (32). Regarding the latter, although figures illustrating the flow of key guideline recommendations are valuable, their interpretation may be ambiguous when related figures are disjointed or when critical information is buried in footnotes or text. The implementation phase of the CTG could benefit from observing clinicians trying to use the guideline and striving to understand and respond to stumbling points. As such, we hope that the initial release of the CTG will function as a living document open to refinement as a result of feedback provided during its implementation.
We have highlighted key aspects of what was done well by the CTG and what could be done better. Because the guideline was not released for public comment before its publication, we hope that a careful discussion about its content will continue, involving patients, health professionals, scientists, health systems, and payers. We offer our initial reactions, aimed at creating momentum for effective guideline implementation and timely updates that will support the application of current best evidence to the care of individual patients.
Dr. Martin is supported by the Pollin Cardiovascular Prevention Fellowship, Marie-Josée and Henry R. Kravis endowed fellowship, and a National Institutes of Health training grant (T32HL07024). Drs. Martin and Jones are listed as coinventors on a pending patent filed by Johns Hopkins University for a method of low-density lipoprotein cholesterol estimation. Dr. Jones is a member of the scientific advisory board for and has received grant support from Atherotech Diagnostic Lab. Dr. Blumenthal is supported by the Kenneth Jay Pollin Professorship in Cardiology. Dr. Blaha is supported by National Institutes of Health grant L30HL110027. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- American College of Cardiology and American Heart Association
- American Association of Clinical Endocrinologists
- atherosclerotic cardiovascular disease
- ATP III
- Adult Treatment Panel III
- coronary heart disease
- Cholesterol Treatment Guideline
- high-density lipoprotein cholesterol
- low-density lipoprotein cholesterol
- National Lipid Association
- Received December 3, 2013.
- Revision received January 28, 2014.
- Accepted February 25, 2014.
- American College of Cardiology Foundation
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