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Alice in Lipidland: The 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol

Editorial Comment

J Am Coll Cardiol, 64 (21) 2193–2195
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Introduction

In the topsy-turvy world of Lewis Carroll’s Alice in Wonderland(1), the Cheshire Cat said, “only a few find the way, some don’t recognize it when they do—some … don’t ever want to.” Such was the status of many healthcare providers and patients in November 2013 at the issuance of the 2013 American College of Cardiology/American Heart Association Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults (2). This was coupled with the Guideline on the Assessment of Cardiovascular Risk (3), using a new risk assessment calculator, the Pooled Cohort Equations (4), to estimate atherosclerotic cardiovascular disease (ASCVD) risk for adults aged 40 to 75 years in the primary prevention setting. ASCVD incorporates stroke events in addition to coronary heart disease events and includes serious nonfatal events, as well as mortality; these additions are designed to reduce disability.

Guideline highlights include the following: focus on managing ASCVD due to elevated low-density lipoprotein cholesterol (LDL-C); citation of inadequate evidence to support raising high-density lipoprotein cholesterol or lowering triglyceride levels; delineation of 4 patient groups at increased absolute ASCVD risk and recommendation of moderate-intensity or high-intensity statins, depending on underlying risk level; and fixed-dose statin therapy, without specific LDL-C targets.

In this issue of the Journal, Maddox et al. (5) offer insights from the NCDR PINNACLE (National Cardiovascular Data Registry Practice Innovation and Clinical Excellence) on implications of these guidelines for contemporary treatment and testing in cardiovascular practice. Data were derived from more than a million patients in 111 cardiology office practices (from 2008 to 2012) with hypertension, coronary artery disease, heart failure, and/or atrial fibrillation. Likely owing to these patient subsets in self-selected cardiology practices, >90% of the population is a secondary prevention cohort, and thus the paper does not address a major focus of the controversy regarding the guideline, that is, primary prevention. Nonetheless, one-third of statin-eligible patients were not receiving statin therapy, and >20% received currently not recommended nonstatin lipid-lowering therapies. As cited in the guideline, nonstatin lipid-lowering therapies lacked benefit, as confirmed by the HPS2-THRIVE (Heart Protection Study 2—Treatment of HDL to Reduce the Incidence of Vascular Events) trial, where niacin plus laropiprant lacked efficacy and conferred risk (6). Analysis of this treatment gap in general medical practices may reveal even greater opportunities for enhancing clinical care quality. Not captured in this database are specific statin drugs and doses, although statin therapy intensity is a new guideline aspect. Despite their pronounced benefit in the diabetic population, 36% of diabetic patients in the PINNACLE registry were not receiving a statin, and this diabetic statin benefit may have been underestimated in a cardiac population. Diabetic patients in endocrinology/internal medicine/primary care practices may more widely differ in statin usage and outcomes. Obviously, substantial differences between primary care (the guideline’s target audience) and cardiology practices are likely.

The guideline advises LDL-C testing to assess adherence to statin therapy, but not for treatment to target; however, 20% of PINNACLE registry patients received currently not recommended repeat LDL-C testing. On the basis of these findings, others will likely examine the overall net cost effect of the new guideline related to increased cost of statin use, reduced cost for nonstatin therapies, reduced use of statin and nonstatin therapies among patients without indications, and reduced costs of LDL-C testing, as well as potential savings from reduced cardiovascular event occurrences.

A limitation of the guideline that selectively disadvantages older adults is that they were virtually absent in the randomized controlled trial data that informed the guideline. Except for PROSPER (Prospective Study of Pravastatin in the Elderly at Risk) (7), which enrolled 8,804 patients aged 70 to 82 years, and SAGE (Study Addressing Goals in the Elderly) (8), with 893 patients 65 to 85 years of age, only 20% to 30% of most primary and secondary prevention lipid trial participants were older than age 70 years (9,10). The contemporary statin treatment-risk paradox is striking; despite the high attributable risk of hypercholesterolemia at elderly age, and the statin-associated reduction in all-cause mortality in this population (10), statin use declines sharply at elderly age. This is despite SAGE’s demonstration of greater benefit in older patients with high-intensity versus moderate-intensity statin therapy. PROSPER showed a 24% coronary mortality decrease for statin versus placebo. Because the randomized controlled trial enrolled few older adults (>75 years), this paucity of evidence enabled only a secondary prevention recommendation for a moderate-intensity statin. The PINNACLE registry data offer little further elucidation. The mean PINNACLE patients’ age was 65.2 years, and only 29.9% were in the Medicare category. The Pooled Cohort Equations provide no ASCVD estimate for those older than age 75 years, who have the highest absolute ASCVD event risk, nor did its antecedent, the Framingham Risk Score. The 2004 update to the National Cholesterol Education Program Adult Treatment Panel III guideline explicitly confirmed that older persons benefit from therapeutic LDL-C lowering (11).

Herein is the window of opportunity for clinician-patient discussions and shared decision making. For the functional elderly adult with few comorbidities, but the highest ASCVD event risk, continuing or initiating high-intensity statins appears prudent, given their documented benefit to safely reduce ASCVD morbidity and mortality. On the contrary, any statin as the 11th or 12th medication for a frail elderly adult with multiple comorbidities and polypharmacy risks appears of limited benefit.

Remember also that the Pooled Cohort Equations provide guidance only for non-Hispanic whites and for blacks. Data are lacking for South Asians, many of whom sustain outcome events and mortality prior to age 40 years. Vulnerable populations merit special attention where observational studies or expert opinion may be all that is currently available. Women with hypertensive and diabetic complications of pregnancy may develop adverse risk profiles shortly after the pregnancy (12). Women with systemic autoimmune disorders (13) are at increased ASCVD risk. We must avoid suggesting that these high-risk populations await their 40th birthdays for risk assessment and appropriate interventions. Age-based discrimination at both ends of the spectrum poses a potentially serious challenge.

And what of patients and goals? How does lack of an LDL-C target relate to motivation to change, or to systems designed to improve adherence to recommended therapies? We employ heart health goals for body mass index, steps/day of exercise, hemoglobin A1c, and blood pressure. Why is LDL-C an orphan? LDL-C measurement is recommended for ascertaining therapy adherence, and the behavioral literature cites the importance of goal-setting to enhancing adherence (14). The REACH (Reduction of Atherothrombosis for Continued Health Registry) report (15) confirms the association of increased adverse events with nonadherence to secondary prevention therapies and recommends targeted interventions for high-risk populations; goal-setting and periodic reassessment may be components of such interventions. Correlates of LDL-C level and ASCVD events are abundant (16), even at elderly age, and in both primary and secondary prevention settings, without evidence of an LDL-C threshold in the 170,000 Cholesterol Treatment Trialists’ Collaboration participants (17). This epidemiologic evidence should help guide physician-patient conversations addressing LDL-C management and related benefits and risks.

In contrast, the European Guidelines on cardiovascular disease prevention in clinical practice (version 2012) recommend intervention strategies as a function of total cardiovascular risk (based on SCORE [Systematic COronary Risk Evaluation]) calculations and LDL-C levels; they identify no differences between younger and older age groups in the benefits of cholesterol lowering, even among individuals >75 years of age. LDL-C is the recommended primary lipid analysis for screening and risk estimation, as well as the treatment target (18). The International Atherosclerosis Society also uses LDL-C targets based on risk status with LDL-C as the major target for lipid-lowering therapy and advises statins as the initial pharmacological intervention (19).

The guideline addresses the 50% anticipated LDL-C reduction with a high-intensity statin and 30% to <50% reduction with a moderate-intensity statin. Guidance is needed for adherent patients who fail to attain this estimated percentage LDL-C reduction. Patient-provider conversations should address increasing statin intensity and/or dosage versus adding a nonstatin drug.

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Footnotes

Dr. Wenger has received research grants and contracts from and served on the Trial Steering Committees and Trial Data Safety and Monitoring Boards for Gilead Sciences, National Heart, Lung, and Blood Institute, Pfizer, and the Society for Women's Health Research; and serves as a consultant for Amgen, AstraZeneca, and Gilead Sciences.