Then and Now: ATP III vs. IV

Comparison of ATP III and ACC/AHA Guidelines

The American College of Cardiology (ACC) and the American Heart Association (AHA) recently released new guidelines for treatment of high blood cholesterol.1 These guidelines were designed to update the previous Adult Treatment Panel III (ATP III) report of the National Cholesterol Education Program (NCEP).2 The ACC/AHA guidelines in fact constitute a new paradigm for cholesterol management. Before comparing the new guidelines with ATP III a few comments about ACC/AHA recommendations may be in order.

The most recent guideline update process was started several years ago under the auspices of the National Heart Lung and Blood Institute (NHLBI). The so-called "ATP IV" panel followed the "rules" for guideline development published by a committee of the Institute of Medicine (IOM) (http://www.iom.edu/Reports/2011/Clinical-Practice-Guidelines-We-Can-Trust.aspx). The IOM emphasized the necessity for "evidence-based medicine" in guideline development. In other words, recommendations should be based mainly on evidence obtained by randomized clinical trials (RCTs). The virtual exclusion of other types of evidence greatly restricted the scope of the new guidelines. This means that the new guidelines left clinicians in the position of having to use their own clinical judgment to arrive at many clinical decisions instead of having science-based guidance to inform these clinical choices.

Recently, the NHLBI made a decision to discontinue the development of clinical guidelines and instead to provide their evidence review to the ACC and AHA. These two organizations transformed NHLBI's evidence reviews into treatment guidelines.

In contrast, the ATP III panel made use of all types of relevant science. It emphasized RCTs, but where appropriate, used epidemiological data, genetic and metabolic studies, and various in vivo and in vitro investigations to flesh out the guidelines. Evidence statements based on various types of scientific data were developed to stand behind recommendations.

Both ATP III and ACC/AHA guidelines emphasize the value of lifestyle intervention. An interesting aspect of the ACC/AHA guidelines is that lifestyle is promoted without RCT evidence. In so doing, the new guideline panel broke their own evidence-based rules. Seemingly, these rules are applied only to drug therapy. Drug recommendations apply only to statins, which have the strongest RCT evidence. The other lipid-lowering drugs—bile acid sequestrants, ezetimibe, fibrates, and nicotinic acid—were largely discounted because of lack of sufficient RCT studies. Still, these drugs can be used if deemed appropriate by clinical judgment. In the discussion to follow, several specific aspects of comparison of the two sets of guidelines can be reviewed.

Low-Density Lipoproteins (LDL) & Atherosclerotic Cardiovascular Disease (ASCVD)

ATP III identified elevated LDL as a major cause of ASCVD. This relationship is seen most dramatically in patients with homozygous or heterozygous familial hypercholesterolemia (FH). In such patients, premature atherosclerosis commonly occurs in the absence of all other risk factors. Other forms of hypercholesterolemia likewise can produce premature ASCVD. Demonstration that a high LDL causes atherosclerosis further comes from animal studies and human epidemiology. Finally, RCTs teach us that the more the LDL is lowered through intervention the greater is the reduction in risk for ASCVD. Congruence of these different lines of evidence makes LDL the centerpiece of ATP III. The panel concluded that any modality that lowers LDL-C will reduce the risk for CHD in proportion to the extent of lowering; therapeutic modalities include both diets and drugs.

The ACC and AHA do not make LDL the centerpiece of their guidelines. They note that lowering of LDL could be beneficial, but adherence to the IOM paradigm makes LDL irrelevant to guideline development. Instead, they make statins the linchpin of their recommendations. Whether statins act through LDL lowering is of no consequence to the new guidelines. ACC/AHA guidelines largely disregard any role for LDL because of their focus on the efficacy of particular drugs per se. By moving away from the connection between LDL and ASCVD risk, the ACC/AHA has departed markedly from previous cholesterol guidelines; this will be the case as long as RCTs are the sole basis of so-called "cholesterol guidelines." In this framework, it is hard to see how atherogenic lipoproteins or lifestyle intervention can ever stand up to drug therapy in prevention of ASCVD.

The new guidelines have abandoned LDL targets of therapy in favor of simply using a dose of statin to treat the patient. But is the achieved risk reduction adequate? ATP III helps the clinician answer this crucial question by reference to the LDL goal, but the new guidelines are agnostic on this point. In addition, the approach of the new guidelines makes cholesterol management quite different from the established and familiar clinical method of managing risk factors such as high blood pressure by setting therapeutic goals. Clinicians may not find the new approach comfortable or easy to implement. The new guidelines do not provide ample guidance on evaluating and monitoring efficacy of therapy.

Secondary Prevention

ATP III and its 2005 update3 set a goal for LDL-C at < 100 mg/dL for high-risk patients, especially those with established ASCVD. Patients with diabetes and a 10-year risk greater than 20% further counted as high-risk patients. Moreover, for those considered to be at very high-risk (i.e., ASCVD + multiple risk factors), a goal of < 70 mg/dL was considered reasonable. In fact, this includes most patients with ASCVD. The LDL-C goal of < 70 mg/dL is based on RCTs, plus meta-analysis and subgroup analysis of RCTs. High-intensity statins on average lower LDL-C to near 70 mg/dL. Even so, a sizable portion of patients treated with high intensity statins fail to attain an LDL-C of < 70 mg/dL. In such patients, ATP III allowed for the addition of a second LDL-lowering drug to attain greater reduction of LDL-C.

ACC/AHA guidelines recommended high-intensity statins in patients with established ASCVD. This recommendation will substantially reduce risk. Nonetheless patients who have a high baseline LDL-C likely will not receive the full benefit of LDL-C lowering because non-statin drugs are not explicitly recommended. This is one area where RCT evidence on statin efficacy and a robust body of scientific evidence on LDL-lowering efficacy are not in accord.

Primary Prevention

Both ATP III and ACC/AHA guidelines carried out 10-year risk assessment to guide drug therapy. ATP III recommended consideration of drug therapy when 10-year risk for CHD was ≥ 10%. ACC/AHA set a threshold for statin drugs at 7.5% for ASCVD. Even ≥5% risk was considered a therapeutic option for statin therapy. ATP III set the 10% risk threshold based on efficacy and cost effectiveness of drug treatment. The ACC/AHA threshold was based on statin efficacy. For higher risk patients, ATP III allowed starting a drug at LDL-C > 100 mg/dL, whereas ACC/AHA starts statins at LDL-C > 70 mg/dL. The latter value is justified by the more recent results of the JUPITER trial,4 which showed efficacy in patients with LDL-C < 100 mg/dL. ACC/AHA's reducing both the projected 10-year risk threshold and the drug initiation level of LDL-C will expand use of statins over that recommended by ATP III. At the time of ATP III, JUPITER results were not available to expand use of LDL-lowering drugs. Whether the expanded use of drugs is cost effective in a broad sense or will be accepted by lower risk persons are not addressed by the ACC/AHA panel.

Risk Assessment

ATP III used Framingham risk scoring to estimate 10-year risk for CHD. ACC/AHA added stroke to CHD, and developed a new algorithm for 10-year risk for ASCVD. This algorithm was constructed from five prospective studies, including two Framingham studies and all funded by NHLBI 5. A recent paper by Ridker and Cook6 claimed that the ACC/AHA algorithm overestimates the risk by about two-fold, compared to three other American populations more recently studied. This accords with other reports that risk in Western Europeans is only about 50% that estimated by Framingham scoring population.7-13 If the ACC/ACC algorithm overestimates risk, the number of lower risk individuals who will be eligible for drug therapy will be further augmented. Clearly, a reliable risk assessment tool for the United States is needed.

Older Persons

Since risk increases with age, there will be a progressive increase in the number of people of advancing age eligible for statins. Age becomes the dominant factor in the ACC/AHA algorithm. Eventually everyone becomes statin eligible by this algorithm — most men in their 60s and more women in their 70s. Certainly not all men and women will benefit from statins. Unless a better means of risk assessment is developed, unnecessary treatment will be common in older persons who have very little coronary or carotid atherosclerosis. One solution is measurement of coronary artery calcium (CAC). CAC scoring will allow for more targeted therapy for those persons who actually have coronary atherosclerosis. A recent publication demonstrates the utility of CAC in differentiating between those who will and who will not suffer CHD.14 If CAC is not available, using a higher 10-year risk by the AHA/ACC algorithm for statin treatment in older persons without clinical ASCVD seems reasonable, e.g., 15-20%. This risk threshold should help to overcome the overestimation of any risk by the ACC/AHA algorithm and more likely will identify those with significant atherosclerosis.

Middle Aged Persons

For this age group, ACC/AHA guidelines are similar to ATP III except that persons with lower risk and lower LDL-C will qualify for statin therapy. Since stoke is relatively uncommon in middle age, risk assessment for ASCVD equates closely to risk for CHD. For any 10-year risk estimate, middle-aged persons will have a higher lifetime risk than older people. The risk algorithm is also more likely to identify those with subclinical atherosclerosis because age will be less of a confounding risk factor. To account for over-prediction of risk by the ACC/AHA algorithm, a 10-year threshold for statin therapy in the range of 10-15% seems reasonable. But again, CAC scoring if available would be useful detecting finding persons who are developing significant atherosclerosis.

Young Adults

Since RCTs generally have recruited few individuals < 40 years, ACC/AHA is silent on this age range. ATP III recommended testing for lipoproteins every five years stating at age 20. Other risk factors likewise should be sought in young adults. Risk factors clearly associate with development of atherosclerosis in the age range of 20-39 years.14 All elevated risk factors deserve intervention in young adults, by lifestyle intervention at a minimum. ATP III stresses the importance of early intervention on risk factors; ACC/AHA guidelines do not. Those with hypercholesterolemia (i.e., LDL-C levels ≥ 160 mg/dL), especially deserve intensive intervention including drug therapy if other risk factors are present. Ten-year risk estimates are of little value in this age range; but the Framingham study 16 documented a high lifetime risk is present when cholesterol levels are relatively high.

Genetic Dyslipidemias

ACC/AHA guidelines did not comment on genetic dyslipidemias. ATP III offered recommendations on treatment of several of atherogenic dyslipidemias, including hypertriglyceridemias. The absence of advice on dyslipidemias in the ACC/AHA report requires that physicians resort to other sources of information. ATP III is one useful source.

Metabolic Syndrome

ATP III highlighted the role of the metabolic syndrome as a multiplex risk factor for ASCVD. This importance was subsequently confirmed by the AHA and NHLBI,17 and several international organizations.18 The presence of this syndrome essentially doubles the risk for ASCVD and is a major target for lifestyle intervention. ACC/AHA guidelines seemingly discount the metabolic syndrome because of a lack of clinical trials that specifically target it with drug therapy. The metabolic syndrome nonetheless remains a major cardiovascular risk factor that needs clinical attention.

Summary

Although there are similarities between ATP III and ACC/AHA guidelines, the two are fundamentally different. ATP III is the summation of several decades of research on the relation of atherogenic lipoproteins to ASCVD. It is based on the concept that lowering atherogenic lipoproteins will prevent ASCVD. ACC/AHA guidelines under the influence of an IOM paradigm are transformed into statin treatment instructions. They give lip service to lifestyle intervention but are embarrassed by a lack of RCTs to underpin lifestyle recommendations. They further can be questioned because they make risk assessment based on older data that may not be suitable for the current US population. Since the ACC/AHA guidelines depend entirely on RCTs, they should not be considered to be comprehensive cholesterol guidelines. Therefore, if using these guidelines, the physician must rely on a heavy dose of clinical judgment. ATP III is still useful for guiding the physician's clinical judgment.


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. J Am Coll Cardiol 2013. [Epub Ahead of Print].
  2. NCEP. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). 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) final report. Circulation 2002;106:3143-421.
  3. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Grundy SM, Cleeman JI, Merz CN, Brewer HB Jr, Clark LT, Hunninghake DB, Pasternak RC, Smith SC Jr, Stone NJ; Coordinating Committee of the National Cholesterol Education Program. J Am Coll Cardiol. 2004 Aug 4;44(3):720-32.
  4. Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359:2195-207.
  5. Goff DC Jr, Lloyd-Jones DM, Bennett G, et al.. 2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013. [Epub ahead of print]
  6. Ridker PM, Cook NR. Statins: new American guidelines for prevention of cardiovascular disease. Lancet 2013;382:1762-1765.
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  11. Menotti A, Puddu P E, Lanti M. Comparison of the Framingham risk function‐based coronary chart with risk function from an Italian population study. Eur Heart J 2000;21:365-370.
  12. Laurier D, Nguyen P C, Cazelles B, et al. Estimation of CHD risk in a French working population using a modified Framingham model. The PCV-METRA Group. J Clin Epidemiol 1994; 471:353-1364.
  13. Hense H W, Schulte H, Lowel H, et al. Framingham risk function overestimates risk of coronary heart disease in men and women from Germany—results from the MONICA Augsburg and the PROCAM cohorts. Eur Heart J 2003;24:937-945.
  14. Budoff MJ, Nasir K, McClelland RL, Detrano R, Wong N, Blumenthal RS, Kondos G, Kronmal RA. Coronary calcium predicts events better with absolute calcium scores than age-sex-race/ethnicity percentiles: MESA (Multi-Ethnic Study of Atherosclerosis). J Am Coll Cardiol 2009;53:345-52.
  15. McMahan CA, Gidding SS, Fayad, ZA, Zieske AW, Malcom GT, Tracy RE, Strong JP, McGill HC Jr. Risk scores predict atherosclerotic lesions in young people. Arch Intern Med 2005;165:883-90.
  16. Lloyd-Jones DM, Wilson PW, Larson MG, Leip E, Beiser A, D'Agostino RB, Cleeman JI, Levy D. Lifetime risk of coronary heart disease by cholesterol levels at selected ages. Arch Intern Med 2003;163:1966-72.
  17. Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, Gordon DJ, Krauss RM, Savage PJ, Smith SC Jr, Spertens JA, Costa F; American Heart Association; National Heart, Lung, and Blood Institute; Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement [published corrections arrear in Circulation, 2005; 112:3297 and Circulation, 2005;112:e298]. Circulation, 2005:112:2735-2752.
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Clinical Topics: Clinical Topic Collection: Dyslipidemia, Lipid Metabolism, Nonstatins, Novel Agents, Statins

Keywords: Adenosine Triphosphate, Atherosclerosis, Cholesterol, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Institute of Medicine (U.S.), Lipoproteins


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