The 2013 ACC/AHA Guidelines on the Treatment of Blood Cholesterol: Questions, Questions, Questions Henry N. Ginsberg Circ Res. 2014;114:761-764 doi: 10.1161/CIRCRESAHA.114.303398 Circulation Research is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2014 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7330. Online ISSN: 1524-4571
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circres.ahajournals.org/content/114/5/761
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Perspectives The 2013 ACC/AHA Guidelines on the Treatment of Blood Cholesterol Questions, Questions, Questions Henry N. Ginsberg
W
hen I was asked to write this Perspective on the 2013 American College of Cardiology (ACC)/American Heart Association (AHA) guidelines,1 I wondered why any reasonable person would agree to do so? It is nice to have your thoughts and opinions in a prestigious journal read by your closest peers, but could it be anything more than a lose-lose situation? I decided, therefore, to preface the perspective with several disclosures. First, I was a member of the original Adult Treatment Panel (ATP) guidelines committee—on the Drug Treatment Subcommittee.2 I was never again asked to be on the committee, but that rejection has had no effect on what I have written here. Second, I think that physician–scientists have the responsibility to integrate all available data, with appropriate priorities, and draw conclusions that can be offered to patients, clinicians, and the world-at-large. So let me state that, based on what I have integrated from a variety of sources for the past 40 years, I have concluded that lowering low-density lipoprotein cholesterol (LDL-C) reduces the risk for atherosclerotic cardiovascular disease (ASCVD), and that the level of LDL-C is important—lower is better. Third, as someone who led a major clinical trial—Action to Control Cardiovascular Risk in Diabetes Lipid3—I know that although randomized clinical trials (RCTs) provide the best evidence for the efficacy and safety of an intervention, each and every RCT has deficiencies. We must avoid, therefore, the tyranny of RCT evidence-based dogma. Fourth, at the end of this piece is my official Disclosure, a listing of my pharmaceutical company relationships. Suffice it to say that all of us who have such relationships must carefully look in the mirror when we evaluate guidelines. However, the same is true for our colleagues who avoid, as part of their career paths, all such industry relationships. Finally, I want to say how much I respect the effort that the panel made for the past several years in generating these new guidelines.
2006) or his book, The Cholesterol Wars: The Skeptics versus the Preponderance of Evidence,4 should do so to place the new guidelines within the framework of the preceding 100 years of preclinical and clinical science, demonstrating both the link between LDL-C and ASCVD, and our ability to reduce the incidence of the latter by lowering blood levels of the former. But individuals who are seriously considering the value and validity of the new guidelines should also review the publications summarizing the first 3 National Cholesterol Education, Adult Treatment Panel guidelines,2,5,6 as well as the modification of those guidelines published in 20047 and the AHA/ACC guidelines published in 2006.8 A close examination of how the guidelines matured during the previous 25 years will facilitate greatly your interpretation of the 2013 version.
Historical Perspective
Some say it is because these new guidelines, unlike the previous guidelines, are strictly and rigorously evidence based, but I am not sure that is completely true. In ATP I, published in 1988,2 the opening paragraph states, as facts, that LDL causes coronary heart disease (CHD), that risk for CHD increases as total cholesterol and LDL-C levels rise, and that lowering LDL reduces the incidence of CHD. The first 2 statements derived from a large base of preclinical and clinical/observational evidence. The last point was based on the results of the Coronary Primary Prevention Trial, the first large (n=3600) RCT demonstrating that lowering LDL-C (with cholestyramine, a bile acid sequestrant) reduced CHD risk.9 Indeed, the impetus to develop the guidelines was the outcome of that iconic RCT. ATP II, published in 1993,5 did not have additional RCTs to support major changes, so the panel chose only to refine the first guidelines
Anyone who has not read the series of 5 reviews by Steinberg in the Journal of Lipid Research (published between 2004 and The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. From the Department of Medicine, The Irving Institute for Clinical and Translational Research, Columbia University College of Physicians and Surgeons, New York. Correspondence to Henry N. Ginsberg, MD, Department of Medicine, The Irving Institute for Clinical and Translational Research, Columbia University College of Physicians and Surgeons, New York, NY 10032. E-mail [email protected] (Circ Res. 2014;114:761-764.) © 2014 American Heart Association, Inc. Circulation Research is available at http://circres.ahajournals.org DOI: 10.1161/CIRCRESAHA.114.303398
Questions, Questions, Questions After reading the entire guidelines several times, I had to decide the depth of my critique. As I formulated my approach, I realized that Passover, the Jewish holiday commemorating the escape of the Israelites from Egypt, could serve as a structure for my perspective. It seems to me that the AHA/ACC panel viewed as their goal an escape from a past filled with LDL-C cut points and targets, parting the waters so to speak, as they moved us from 5 prior guideline statements into a new era of strictly evidence-based medicine, which will ensure that only those most likely to benefit will be treated. So picture yourself at the Passover Seder where, at a long table with too many people seated around too much food, the youngest family member, instead of asking the traditional 4 questions about the Passover holiday, asks about the guidelines.
Grandpa, Why Are These Guidelines Different From All the Previous Guidelines?
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762 Circulation Research February 28, 2014
Nonstandard Abbreviation and Acronyms ACC AHA ASCVD ATP CHD LDL-C RCT
American College of Cardiology American Heart Association atherosclerotic cardiovascular disease Adult Treatment Panel coronary heart disease low-density lipoprotein cholesterol randomized clinical trials
in several ways, including the identification of people with existing CHD as being at particularly high risk for additional events. ATP II also introduced the terms Primary and Secondary Prevention to the guidelines. The identification of a high-risk group with existing CHD and the division of people into those with and without pre-existing disease are key components of the new guidelines. In ATP III, published in 2001,6 the opening paragraph noted that “The full ATP III document is an evidence-based and extensively referenced report…” ATP III was supported by the results of 5 major statin RCTs: Scandinavian Simvastatin Survival Study,10 West of Scotland Coronary Prevention Study,11 Cholesterol and Recurrent Events,12 LongTerm Intervention with Pravastatin in Ischemic Disease,13 and Air Force/Texas Coronary Atherosclerosis Prevention Study.14 Those studies provided the panel with the evidence they needed to increase the level of intensity of treatment recommendations. In addition, ATP III introduced the Framingham Score as a refinement to counting risk factors; the new guidelines use the Pooled Cohort Equation. The stimulus for Implications of Recent Trials for the NCEP ATP III Guidelines in 20047 was the publication of 5 additional major statin-RCTs completed after the release of ATP III: Heart Protection Study (HPS),15 Prospective Study of Pravastatin in the Elderly at Risk (PROSPER),16 Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial -Lipid Lowering Trial,17 Anglo-Scandinavian Cardiac Outcomes Trial -Lipid Lowering Arm,18 and Pravastatin or Atorvastatin Evaluation and Infection Therapy-TIMI22 (PROVE IT-TIMI22).19 On the basis of the evidence provided by these studies, the panel of National Institutes of Health, AHA, and ACC experts increased the level of intensity for the treatment of LDL-C, particularly in those people with pre-existing disease and in those with multiple risk factors. Finally, the 2006 AHA/ACC Guidelines for Secondary Prevention for Patients with Coronary and Other Atherosclerotic Vascular Disease8 raised the level of treatmentintensity even further, based on Treat to New Targets (TNT)20 and Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL).21 Importantly, the AHA/ACC panel used the same classification system for evidence-based guidelines that the most recent panel used (compare references 1 and 8). So it does not seem that the use of evidence-based recommendations is unique, or novel, to the new guidelines. Rather, the new guidelines differ from all the previous ones because the panel decided on a unique interpretation of essentially the same body of evidence used previously. In particular, the same evidence used as the basis for the 2006 AHA/ACC Guidelines led the new panel to change our approach dramatically to the treatment of LDL-C to prevent ASCVD.
In All Previous Guidelines, We Used LDL-C Cut Points to Initiate Treatments; Why Are We Now Focusing on 4 Groups of Patients? Although this seems to be a significant change, it is actually an aspect of the new guidelines that makes sense as a natural evolution of our approach to treatment. In ATP I, levels of total cholesterol were chosen as cut points to initiate diet and, if necessary, drug therapy, based on risk estimates for ASCVD derived from the Multiple Risk Factor Intervention Trial study.22 The LDL-C levels for each risk-group were approximated from levels of total cholesterol. Because these cut points for starting treatments have been iteratively modified based on a series of RCTs that showed efficacy with lower and lower starting LDL-C levels, it seems reasonable to move from 3 or 4 LDL-C cut points to 4 groups of individuals based on risk for having a CHD or ASCVD event (Table). I think that the new guidelines make it easier to identify individuals requiring treatment and should, as the panel hopes, lead to treatment of those “most likely to benefit.” Not everyone agrees with this new approach, with some saying it will double the number of individuals receiving statins.23 My sense, as well as that of the panel,24 is that about the same number of individuals will be treated under the new guidelines (I am ignoring the debate about the accuracy of the risk calculator—way above my pay scale). Overall, I support the panels approach to identify risk, rather than the level of LDL-C, as the key determinant of treatment.
In All Previous Guidelines, We Had LDL-C Targets for Therapies; Why Are We Now Just Treating People With Statins and Not Worrying About Where Their LDL-C Levels End Up? As much as I agree with the shift from LDL-C cut points for starting treatment to 4 risk groups, I disagree completely with moving from LDL-C targets to a strategy that says “since statins work regardless of the starting LDL-C, why worry about the final levels of these atherogenic lipoproteins” (my quotes). The conclusion by the panel that because they could not find evidence from any RCT that titration of LDL-C to a specific target further reduced CHD or ASCVD events beyond that achieved by just giving a statin when compared with placebo is a clear example of the tyranny of evidence-based dogma (ie, because there has not been a titration trial targeting a specific LDL-C level that would be the same for every individual in the treatment group, we should not have LDL-C targets). I agree that RCTs most often test drugs, not strategies, but you cannot ignore the meta-analysis of 169 138 participants in 26 statin trials published by the Cholesterol Treatment Trialists (CTT) Collaboration,25 demonstrating continuously lower event rates with progressively lower achieved LDL-C concentration. You cannot ignore TNT,20 PROVE IT-TIMI 22,19 and IDEAL,21 which demonstrated directly that achieving a greater reduction in LDL-C, which equated to a lower LDL-C, was associated with greater reductions in events. Panel members decided that those studies simply proved that high intensity was better than low- or moderate-intensity statin therapy: I find that wrong-headed. In the opening paragraph of TNT,20 the authors state “We prospectively assessed the efficacy and safety of lowering LDL cholesterol levels below 100 mg per deciliter (2.6 mmol per liter) in patients with stable coronary
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Ginsberg The 2013 AHA/ACC Guidelines 763 Table. Four Groups Meeting Criteria for Treatment With Statins to Reduce LDL-C Levels 1. Individuals with clinical ASCVD 2. Individuals with primary elevations of LDL-C >190 mg/dL 3. Individuals with diabetes mellitus, aged 40–75 y, with LDL-C 70–189 mg/dL 4. Individuals without ASCVD or diabetes mellitus, with LDL-C 70–189 mg/dL, and estimated 10-y ASCVD risk of ≥7.5% LDL-C indicates low-density lipoprotein-cholesterol.
heart disease (CHD).” The background section of PROVE IT19 states the study “…was designed to compare the standard degree of LDL cholesterol lowering to approximately 100 mg per deciliter with the use of 40 mg of pravastatin daily with more intensive LDL cholesterol lowering to approximately 70 mg per deciliter with the use of 80 mg of atorvastatin daily as a mean of preventing death or major cardiovascular events in patients with an acute coronary syndrome.” These statements indicate clearly that the goal of the investigators was to test the hypothesis that a lower LDL-C, not simply a higher dose of statin, is better. Finally, to this point, the panel uses the CTT meta-analysis25 inconsistently; they quote CTT data to support the changes they have made, that is, why they shifted away from initial LDL-C cut points, or why high-intensity statin is better than low-intensity statin, but pass by statements made by the CTT authors that lowering LDL beyond even the present targets, possibly with combinations of potent statins and nonstatin agents, will result in even greater benefit (my rewording of the last paragraph of 26). So why did the panel, in the face of significant evidence, abandon completely the LDL-C targets that were central to all previous guidelines. Despite what is stated repeatedly in the new guidelines about the lack of evidence, my suspicion, which I am allowed to make public in this perspective, was that dropping targets allowed the panel to avoid a serious discussion of nonstatin agents. The issue of nonstatin drugs is clearly complex, but it seems that the decision of panel to provide a simple one-size fits all solution, that is, statin monotherapy or no therapy, was a way to escape a difficult situation. The argument that there are no data in support of adding niacin is based on the absence of positive outcomes of 2 RCTs with niacin when mean LDL-C levels were already 100 mg/dL.26 The lack of any recommendations on bile acid sequestrants ignores the CPPT.9 The argument against ezetimibe is valid if based on the absence of RCT data, but much less strong if we consider the 100 years of science, validating the hypothesis that lowering LDL-C reduces CHD. Of note, the guidelines do support the use of high-intensity statin and, if needed, multiple drugs for individuals with familial hypercholesterolemia, despite the fact that not even statin treatment has been proven, in an RCT, to prevent CHD events in patients with familial hypercholesterolemia. The panel appropriately supported these latter recommendations with an National Heart, Lung, and Blood Institute grade of Expert Opinion and an ACC/AHA class of recommendation of IIa/IIb; they could have done the same for the use of LDL-C targets. Overall, I believe strongly that, while
not perfect, targets are crucial components of our approach to treatment of LDL-C to prevent CHD.
In All Previous Guidelines, Different Statin Intensity Was Linked to LDL-C Levels Cut Points and Targets; If We No Longer Use Either of Those, Why Do We Still Have Different Levels of StatinTreatment Intensity? I do not understand this one at all. If the panel chose not to have targets for LDL-C and yet did refer to the CTT metaanalysis25 several times as evidence that you both get benefit irrespective of the starting LDL-C and that lower absolute rates of events are observed at lower levels of LDL-C, why did they not at least support high intensity, maximal LDL-C lowering to all 4 groups. I think that our colleagues in Canada, who offered either a goal of ≈80 mg/dL or ≥50% LDL-C lowering made better choices.27
In All Previous Guidelines, There Were No Hard Cutoffs for Age; Why Do We Now Have 75 Years as a Defined Upper Limit for the Guidelines Main Recommendations? The matzoh-ball soup is getting cold so I will be brief. When I look at HPS,15 PROSPER,16 and the CTT meta-analysis,25 and when I consider that there is no age limit for revascularization procedures, I will treat higher risk individuals at all ages.
What the Future Holds At the Seder, we leave the door open for the Prophet Elijah to join us for a glass of wine. The new guidelines also left the door open (Section 9, Gaps and Future Research Needs). In my view, however, they also left themselves and the guidelines process exposed to a drastic reversal when results of studies presently underway are available. I am not sure if Examining Outcomes in Subjects With Acute Coronary Syndrome: Vytorin (Ezetimibe/Simvastatin) vs Simvastatin will be positive, but it is likely that trials with cholesteryl ester transfer protein inhibitors or proprotein convertase subtilisin/kexin type 9 inhibitors will show significant benefit of further lowering of LDL-C on the background of statin therapy. Because the new guidelines have abandoned LDL-C targets, the next panel will either have to reinstate them or be forced to develop an algorithm where some patients will receive these new agents on top of statins irrespective of LDL-C levels. It is unfortunate that by deciding not to recommend LDL-C targets even as Expert Opinion, the panel opened the door so little that Elijah may have to knock it completely down to enter and drink his wine.
Disclosures The author has had, during the past 12 months, relationships (grant funding, consulting, lectures) with the following pharmaceutical companies: AstraZeneca, Boerhinger-Ingelheim, BristolMyersSquibb, Genentech/Roche, Genzyme, ISIS, Janssen, Kowa, Merck, Novartis, Pfizer, Regeneron, and Sanofi.
References 1. 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.
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764 Circulation Research February 28, 2014 [Epub ahead of print, November 12, 2013]. Circulation. doi: 10.1161/ 01.cir.0000437738.63853.7a: http://circ.ahajournals.org/content/early/ 2013/11/11/01.cir.0000437738.63853.7a.citation. Accessed February 4, 2014. 2. Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Arch Intern Med. 1988;148:36–69. 3. Ginsberg HN, Elam MB, Lovato LC, et al.; ACCORD Study Group. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010;362:1563–1574. 4. Steinberg D. The Cholesterol Wars: The Cholesterol Skeptics vs the Preponderance of Evidence. New York, NY: Academic Press; 2007. 5. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Summary of the Second Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). JAMA. 1993;269:3015–3023. 6. Expert Panel on Detection, Evaluation, and 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). JAMA. 2001;285:2486–2497. 7. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Arterioscler Thromb Vasc Biol. 2004;24:e149–61. 8. AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update: endorsed by the National Heart, Lung, and Blood Institute. Circulation. 2006;113:2363–2372. 9. The Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in incidence of coronary heart disease. JAMA. 1984;251:351–364. 10. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, McKillop JH, Packard CJ. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med. 1995;333:1301–1307. 11. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383–1389. 12. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med. 1998;339:1349–1357. 13. Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JMO, Wun C-C, Davis BR, Braunwald E. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med. 1996;334:1001–1009. 14. Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, Langendorfer A, Stein EA, Kruyer W, Gotto AM Jr. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA. 1998;279:1615–1622. 15. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360:7–22.
16. Shepherd J, Blauw GJ, Murphy MB, 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. Lancet. 2002;360:1623–1630. 17. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). JAMA. 2002; 288:2998–3007. 18. Sever PS, Dahlöf B, Poulter NR, Wedel H, Beevers G, Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, McInnes GT, Mehlsen J, Nieminen M, O’Brien E, Ostergren J; ASCOT Investigators. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet. 2003;361:1149–1158. 19. Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, Joyal SV, Hill KA, Pfeffer MA, Skene AM; Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350:1495–1504. 20. LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC, Gotto AM, Greten H, Kastelein JJ, Shepherd J, Wenger NK; Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352:1425–1435. 21. Pedersen TR, Faergeman O, Kastelein JJ, Olsson AG, Tikkanen MJ, Holme I, Larsen ML, Bendiksen FS, Lindahl C, Szarek M, Tsai J; Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) Study Group. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. JAMA. 2005;294:2437–2445. 22. Multiple risk factor intervention trial. Risk factor changes and mortality results. Multiple Risk Factor Intervention Trial Research Group.JAMA. 1982; 248:1465–1477. 23. Abramson JD, Redberg RF. Op-Ed Contributors: Don’t Give More Patients Statins. New York, NY: New York Times; 2013. Published November 13, 2013. 24. Lloyd-Jones, D, Goff, D, Stone, NJ. Statins, risk assessment, and the new American prevention guidelines [Epub ahead of print December 3, 2013]. Lancet. doi: 10.1016/S0140-6736(13)62348-X. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2813%2962348-X/ fulltext?rss=yes. Accessed February 4, 2014. 25. Baigent C, Blackwell L, Emberson J et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010;376:1670–1681. 26. Coronary Drug Project. Clofibrate and niacin in coronary heart disease. JAMA 1975;231:360–381. 27. Anderson TJ, Grégoire J, Hegele RA, Couture P, Mancini GB, McPherson R, Francis GA, Poirier P, Lau DC, Grover S, Genest J Jr, Carpentier AC, Dufour R, Gupta M, Ward R, Leiter LA, Lonn E, Ng DS, Pearson GJ, Yates GM, Stone JA, Ur E. 2012 update of the Canadian Cardiovascular Society guidelines for the diagnosis and treatment of dyslipidemia for the prevention of cardiovascular disease in the adult. Can J Cardiol. 2013; 29:151–67. Key Words: cardiovascular disease ■ cholesterol ■ low-density-lipoprotein ■ risk ■ treatment
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The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circres.ahajournals.org/content/114/5/761
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation Research can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Circulation Research is online at: http://circres.ahajournals.org//subscriptions/
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Perspectives The 2013 ACC/AHA Guidelines on the Treatment of Blood Cholesterol Questions, Questions, Questions Henry N. Ginsberg
W
hen I was asked to write this Perspective on the 2013 American College of Cardiology (ACC)/American Heart Association (AHA) guidelines,1 I wondered why any reasonable person would agree to do so? It is nice to have your thoughts and opinions in a prestigious journal read by your closest peers, but could it be anything more than a lose-lose situation? I decided, therefore, to preface the perspective with several disclosures. First, I was a member of the original Adult Treatment Panel (ATP) guidelines committee—on the Drug Treatment Subcommittee.2 I was never again asked to be on the committee, but that rejection has had no effect on what I have written here. Second, I think that physician–scientists have the responsibility to integrate all available data, with appropriate priorities, and draw conclusions that can be offered to patients, clinicians, and the world-at-large. So let me state that, based on what I have integrated from a variety of sources for the past 40 years, I have concluded that lowering low-density lipoprotein cholesterol (LDL-C) reduces the risk for atherosclerotic cardiovascular disease (ASCVD), and that the level of LDL-C is important—lower is better. Third, as someone who led a major clinical trial—Action to Control Cardiovascular Risk in Diabetes Lipid3—I know that although randomized clinical trials (RCTs) provide the best evidence for the efficacy and safety of an intervention, each and every RCT has deficiencies. We must avoid, therefore, the tyranny of RCT evidence-based dogma. Fourth, at the end of this piece is my official Disclosure, a listing of my pharmaceutical company relationships. Suffice it to say that all of us who have such relationships must carefully look in the mirror when we evaluate guidelines. However, the same is true for our colleagues who avoid, as part of their career paths, all such industry relationships. Finally, I want to say how much I respect the effort that the panel made for the past several years in generating these new guidelines.
2006) or his book, The Cholesterol Wars: The Skeptics versus the Preponderance of Evidence,4 should do so to place the new guidelines within the framework of the preceding 100 years of preclinical and clinical science, demonstrating both the link between LDL-C and ASCVD, and our ability to reduce the incidence of the latter by lowering blood levels of the former. But individuals who are seriously considering the value and validity of the new guidelines should also review the publications summarizing the first 3 National Cholesterol Education, Adult Treatment Panel guidelines,2,5,6 as well as the modification of those guidelines published in 20047 and the AHA/ACC guidelines published in 2006.8 A close examination of how the guidelines matured during the previous 25 years will facilitate greatly your interpretation of the 2013 version.
Historical Perspective
Some say it is because these new guidelines, unlike the previous guidelines, are strictly and rigorously evidence based, but I am not sure that is completely true. In ATP I, published in 1988,2 the opening paragraph states, as facts, that LDL causes coronary heart disease (CHD), that risk for CHD increases as total cholesterol and LDL-C levels rise, and that lowering LDL reduces the incidence of CHD. The first 2 statements derived from a large base of preclinical and clinical/observational evidence. The last point was based on the results of the Coronary Primary Prevention Trial, the first large (n=3600) RCT demonstrating that lowering LDL-C (with cholestyramine, a bile acid sequestrant) reduced CHD risk.9 Indeed, the impetus to develop the guidelines was the outcome of that iconic RCT. ATP II, published in 1993,5 did not have additional RCTs to support major changes, so the panel chose only to refine the first guidelines
Anyone who has not read the series of 5 reviews by Steinberg in the Journal of Lipid Research (published between 2004 and The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. From the Department of Medicine, The Irving Institute for Clinical and Translational Research, Columbia University College of Physicians and Surgeons, New York. Correspondence to Henry N. Ginsberg, MD, Department of Medicine, The Irving Institute for Clinical and Translational Research, Columbia University College of Physicians and Surgeons, New York, NY 10032. E-mail [email protected] (Circ Res. 2014;114:761-764.) © 2014 American Heart Association, Inc. Circulation Research is available at http://circres.ahajournals.org DOI: 10.1161/CIRCRESAHA.114.303398
Questions, Questions, Questions After reading the entire guidelines several times, I had to decide the depth of my critique. As I formulated my approach, I realized that Passover, the Jewish holiday commemorating the escape of the Israelites from Egypt, could serve as a structure for my perspective. It seems to me that the AHA/ACC panel viewed as their goal an escape from a past filled with LDL-C cut points and targets, parting the waters so to speak, as they moved us from 5 prior guideline statements into a new era of strictly evidence-based medicine, which will ensure that only those most likely to benefit will be treated. So picture yourself at the Passover Seder where, at a long table with too many people seated around too much food, the youngest family member, instead of asking the traditional 4 questions about the Passover holiday, asks about the guidelines.
Grandpa, Why Are These Guidelines Different From All the Previous Guidelines?
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762 Circulation Research February 28, 2014
Nonstandard Abbreviation and Acronyms ACC AHA ASCVD ATP CHD LDL-C RCT
American College of Cardiology American Heart Association atherosclerotic cardiovascular disease Adult Treatment Panel coronary heart disease low-density lipoprotein cholesterol randomized clinical trials
in several ways, including the identification of people with existing CHD as being at particularly high risk for additional events. ATP II also introduced the terms Primary and Secondary Prevention to the guidelines. The identification of a high-risk group with existing CHD and the division of people into those with and without pre-existing disease are key components of the new guidelines. In ATP III, published in 2001,6 the opening paragraph noted that “The full ATP III document is an evidence-based and extensively referenced report…” ATP III was supported by the results of 5 major statin RCTs: Scandinavian Simvastatin Survival Study,10 West of Scotland Coronary Prevention Study,11 Cholesterol and Recurrent Events,12 LongTerm Intervention with Pravastatin in Ischemic Disease,13 and Air Force/Texas Coronary Atherosclerosis Prevention Study.14 Those studies provided the panel with the evidence they needed to increase the level of intensity of treatment recommendations. In addition, ATP III introduced the Framingham Score as a refinement to counting risk factors; the new guidelines use the Pooled Cohort Equation. The stimulus for Implications of Recent Trials for the NCEP ATP III Guidelines in 20047 was the publication of 5 additional major statin-RCTs completed after the release of ATP III: Heart Protection Study (HPS),15 Prospective Study of Pravastatin in the Elderly at Risk (PROSPER),16 Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial -Lipid Lowering Trial,17 Anglo-Scandinavian Cardiac Outcomes Trial -Lipid Lowering Arm,18 and Pravastatin or Atorvastatin Evaluation and Infection Therapy-TIMI22 (PROVE IT-TIMI22).19 On the basis of the evidence provided by these studies, the panel of National Institutes of Health, AHA, and ACC experts increased the level of intensity for the treatment of LDL-C, particularly in those people with pre-existing disease and in those with multiple risk factors. Finally, the 2006 AHA/ACC Guidelines for Secondary Prevention for Patients with Coronary and Other Atherosclerotic Vascular Disease8 raised the level of treatmentintensity even further, based on Treat to New Targets (TNT)20 and Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL).21 Importantly, the AHA/ACC panel used the same classification system for evidence-based guidelines that the most recent panel used (compare references 1 and 8). So it does not seem that the use of evidence-based recommendations is unique, or novel, to the new guidelines. Rather, the new guidelines differ from all the previous ones because the panel decided on a unique interpretation of essentially the same body of evidence used previously. In particular, the same evidence used as the basis for the 2006 AHA/ACC Guidelines led the new panel to change our approach dramatically to the treatment of LDL-C to prevent ASCVD.
In All Previous Guidelines, We Used LDL-C Cut Points to Initiate Treatments; Why Are We Now Focusing on 4 Groups of Patients? Although this seems to be a significant change, it is actually an aspect of the new guidelines that makes sense as a natural evolution of our approach to treatment. In ATP I, levels of total cholesterol were chosen as cut points to initiate diet and, if necessary, drug therapy, based on risk estimates for ASCVD derived from the Multiple Risk Factor Intervention Trial study.22 The LDL-C levels for each risk-group were approximated from levels of total cholesterol. Because these cut points for starting treatments have been iteratively modified based on a series of RCTs that showed efficacy with lower and lower starting LDL-C levels, it seems reasonable to move from 3 or 4 LDL-C cut points to 4 groups of individuals based on risk for having a CHD or ASCVD event (Table). I think that the new guidelines make it easier to identify individuals requiring treatment and should, as the panel hopes, lead to treatment of those “most likely to benefit.” Not everyone agrees with this new approach, with some saying it will double the number of individuals receiving statins.23 My sense, as well as that of the panel,24 is that about the same number of individuals will be treated under the new guidelines (I am ignoring the debate about the accuracy of the risk calculator—way above my pay scale). Overall, I support the panels approach to identify risk, rather than the level of LDL-C, as the key determinant of treatment.
In All Previous Guidelines, We Had LDL-C Targets for Therapies; Why Are We Now Just Treating People With Statins and Not Worrying About Where Their LDL-C Levels End Up? As much as I agree with the shift from LDL-C cut points for starting treatment to 4 risk groups, I disagree completely with moving from LDL-C targets to a strategy that says “since statins work regardless of the starting LDL-C, why worry about the final levels of these atherogenic lipoproteins” (my quotes). The conclusion by the panel that because they could not find evidence from any RCT that titration of LDL-C to a specific target further reduced CHD or ASCVD events beyond that achieved by just giving a statin when compared with placebo is a clear example of the tyranny of evidence-based dogma (ie, because there has not been a titration trial targeting a specific LDL-C level that would be the same for every individual in the treatment group, we should not have LDL-C targets). I agree that RCTs most often test drugs, not strategies, but you cannot ignore the meta-analysis of 169 138 participants in 26 statin trials published by the Cholesterol Treatment Trialists (CTT) Collaboration,25 demonstrating continuously lower event rates with progressively lower achieved LDL-C concentration. You cannot ignore TNT,20 PROVE IT-TIMI 22,19 and IDEAL,21 which demonstrated directly that achieving a greater reduction in LDL-C, which equated to a lower LDL-C, was associated with greater reductions in events. Panel members decided that those studies simply proved that high intensity was better than low- or moderate-intensity statin therapy: I find that wrong-headed. In the opening paragraph of TNT,20 the authors state “We prospectively assessed the efficacy and safety of lowering LDL cholesterol levels below 100 mg per deciliter (2.6 mmol per liter) in patients with stable coronary
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Ginsberg The 2013 AHA/ACC Guidelines 763 Table. Four Groups Meeting Criteria for Treatment With Statins to Reduce LDL-C Levels 1. Individuals with clinical ASCVD 2. Individuals with primary elevations of LDL-C >190 mg/dL 3. Individuals with diabetes mellitus, aged 40–75 y, with LDL-C 70–189 mg/dL 4. Individuals without ASCVD or diabetes mellitus, with LDL-C 70–189 mg/dL, and estimated 10-y ASCVD risk of ≥7.5% LDL-C indicates low-density lipoprotein-cholesterol.
heart disease (CHD).” The background section of PROVE IT19 states the study “…was designed to compare the standard degree of LDL cholesterol lowering to approximately 100 mg per deciliter with the use of 40 mg of pravastatin daily with more intensive LDL cholesterol lowering to approximately 70 mg per deciliter with the use of 80 mg of atorvastatin daily as a mean of preventing death or major cardiovascular events in patients with an acute coronary syndrome.” These statements indicate clearly that the goal of the investigators was to test the hypothesis that a lower LDL-C, not simply a higher dose of statin, is better. Finally, to this point, the panel uses the CTT meta-analysis25 inconsistently; they quote CTT data to support the changes they have made, that is, why they shifted away from initial LDL-C cut points, or why high-intensity statin is better than low-intensity statin, but pass by statements made by the CTT authors that lowering LDL beyond even the present targets, possibly with combinations of potent statins and nonstatin agents, will result in even greater benefit (my rewording of the last paragraph of 26). So why did the panel, in the face of significant evidence, abandon completely the LDL-C targets that were central to all previous guidelines. Despite what is stated repeatedly in the new guidelines about the lack of evidence, my suspicion, which I am allowed to make public in this perspective, was that dropping targets allowed the panel to avoid a serious discussion of nonstatin agents. The issue of nonstatin drugs is clearly complex, but it seems that the decision of panel to provide a simple one-size fits all solution, that is, statin monotherapy or no therapy, was a way to escape a difficult situation. The argument that there are no data in support of adding niacin is based on the absence of positive outcomes of 2 RCTs with niacin when mean LDL-C levels were already 100 mg/dL.26 The lack of any recommendations on bile acid sequestrants ignores the CPPT.9 The argument against ezetimibe is valid if based on the absence of RCT data, but much less strong if we consider the 100 years of science, validating the hypothesis that lowering LDL-C reduces CHD. Of note, the guidelines do support the use of high-intensity statin and, if needed, multiple drugs for individuals with familial hypercholesterolemia, despite the fact that not even statin treatment has been proven, in an RCT, to prevent CHD events in patients with familial hypercholesterolemia. The panel appropriately supported these latter recommendations with an National Heart, Lung, and Blood Institute grade of Expert Opinion and an ACC/AHA class of recommendation of IIa/IIb; they could have done the same for the use of LDL-C targets. Overall, I believe strongly that, while
not perfect, targets are crucial components of our approach to treatment of LDL-C to prevent CHD.
In All Previous Guidelines, Different Statin Intensity Was Linked to LDL-C Levels Cut Points and Targets; If We No Longer Use Either of Those, Why Do We Still Have Different Levels of StatinTreatment Intensity? I do not understand this one at all. If the panel chose not to have targets for LDL-C and yet did refer to the CTT metaanalysis25 several times as evidence that you both get benefit irrespective of the starting LDL-C and that lower absolute rates of events are observed at lower levels of LDL-C, why did they not at least support high intensity, maximal LDL-C lowering to all 4 groups. I think that our colleagues in Canada, who offered either a goal of ≈80 mg/dL or ≥50% LDL-C lowering made better choices.27
In All Previous Guidelines, There Were No Hard Cutoffs for Age; Why Do We Now Have 75 Years as a Defined Upper Limit for the Guidelines Main Recommendations? The matzoh-ball soup is getting cold so I will be brief. When I look at HPS,15 PROSPER,16 and the CTT meta-analysis,25 and when I consider that there is no age limit for revascularization procedures, I will treat higher risk individuals at all ages.
What the Future Holds At the Seder, we leave the door open for the Prophet Elijah to join us for a glass of wine. The new guidelines also left the door open (Section 9, Gaps and Future Research Needs). In my view, however, they also left themselves and the guidelines process exposed to a drastic reversal when results of studies presently underway are available. I am not sure if Examining Outcomes in Subjects With Acute Coronary Syndrome: Vytorin (Ezetimibe/Simvastatin) vs Simvastatin will be positive, but it is likely that trials with cholesteryl ester transfer protein inhibitors or proprotein convertase subtilisin/kexin type 9 inhibitors will show significant benefit of further lowering of LDL-C on the background of statin therapy. Because the new guidelines have abandoned LDL-C targets, the next panel will either have to reinstate them or be forced to develop an algorithm where some patients will receive these new agents on top of statins irrespective of LDL-C levels. It is unfortunate that by deciding not to recommend LDL-C targets even as Expert Opinion, the panel opened the door so little that Elijah may have to knock it completely down to enter and drink his wine.
Disclosures The author has had, during the past 12 months, relationships (grant funding, consulting, lectures) with the following pharmaceutical companies: AstraZeneca, Boerhinger-Ingelheim, BristolMyersSquibb, Genentech/Roche, Genzyme, ISIS, Janssen, Kowa, Merck, Novartis, Pfizer, Regeneron, and Sanofi.
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764 Circulation Research February 28, 2014 [Epub ahead of print, November 12, 2013]. Circulation. doi: 10.1161/ 01.cir.0000437738.63853.7a: http://circ.ahajournals.org/content/early/ 2013/11/11/01.cir.0000437738.63853.7a.citation. Accessed February 4, 2014. 2. Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Arch Intern Med. 1988;148:36–69. 3. Ginsberg HN, Elam MB, Lovato LC, et al.; ACCORD Study Group. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010;362:1563–1574. 4. Steinberg D. The Cholesterol Wars: The Cholesterol Skeptics vs the Preponderance of Evidence. New York, NY: Academic Press; 2007. 5. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Summary of the Second Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). JAMA. 1993;269:3015–3023. 6. Expert Panel on Detection, Evaluation, and 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). JAMA. 2001;285:2486–2497. 7. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Arterioscler Thromb Vasc Biol. 2004;24:e149–61. 8. AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update: endorsed by the National Heart, Lung, and Blood Institute. Circulation. 2006;113:2363–2372. 9. The Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in incidence of coronary heart disease. JAMA. 1984;251:351–364. 10. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, McKillop JH, Packard CJ. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med. 1995;333:1301–1307. 11. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383–1389. 12. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med. 1998;339:1349–1357. 13. Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JMO, Wun C-C, Davis BR, Braunwald E. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med. 1996;334:1001–1009. 14. Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, Langendorfer A, Stein EA, Kruyer W, Gotto AM Jr. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA. 1998;279:1615–1622. 15. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360:7–22.
16. Shepherd J, Blauw GJ, Murphy MB, 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. Lancet. 2002;360:1623–1630. 17. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). JAMA. 2002; 288:2998–3007. 18. Sever PS, Dahlöf B, Poulter NR, Wedel H, Beevers G, Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, McInnes GT, Mehlsen J, Nieminen M, O’Brien E, Ostergren J; ASCOT Investigators. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet. 2003;361:1149–1158. 19. Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, Joyal SV, Hill KA, Pfeffer MA, Skene AM; Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350:1495–1504. 20. LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC, Gotto AM, Greten H, Kastelein JJ, Shepherd J, Wenger NK; Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352:1425–1435. 21. Pedersen TR, Faergeman O, Kastelein JJ, Olsson AG, Tikkanen MJ, Holme I, Larsen ML, Bendiksen FS, Lindahl C, Szarek M, Tsai J; Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) Study Group. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. JAMA. 2005;294:2437–2445. 22. Multiple risk factor intervention trial. Risk factor changes and mortality results. Multiple Risk Factor Intervention Trial Research Group.JAMA. 1982; 248:1465–1477. 23. Abramson JD, Redberg RF. Op-Ed Contributors: Don’t Give More Patients Statins. New York, NY: New York Times; 2013. Published November 13, 2013. 24. Lloyd-Jones, D, Goff, D, Stone, NJ. Statins, risk assessment, and the new American prevention guidelines [Epub ahead of print December 3, 2013]. Lancet. doi: 10.1016/S0140-6736(13)62348-X. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2813%2962348-X/ fulltext?rss=yes. Accessed February 4, 2014. 25. Baigent C, Blackwell L, Emberson J et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010;376:1670–1681. 26. Coronary Drug Project. Clofibrate and niacin in coronary heart disease. JAMA 1975;231:360–381. 27. Anderson TJ, Grégoire J, Hegele RA, Couture P, Mancini GB, McPherson R, Francis GA, Poirier P, Lau DC, Grover S, Genest J Jr, Carpentier AC, Dufour R, Gupta M, Ward R, Leiter LA, Lonn E, Ng DS, Pearson GJ, Yates GM, Stone JA, Ur E. 2012 update of the Canadian Cardiovascular Society guidelines for the diagnosis and treatment of dyslipidemia for the prevention of cardiovascular disease in the adult. Can J Cardiol. 2013; 29:151–67. Key Words: cardiovascular disease ■ cholesterol ■ low-density-lipoprotein ■ risk ■ treatment
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