- Email: [email protected]
Alteration of Relation of Atherogenic Lipoprotein Cholesterol to Apolipoprotein B by Intensive Statin Therapy in Patients With Acute Coronary Syndrome (from the Limiting UNdertreatment of lipids in ACS With Rosuvastatin [LUNAR] Trial)
Alteration of Relation of Atherogenic Lipoprotein Cholesterol to Apolipoprotein B by Intensive Statin Therapy in Patients With Acute Coronary Syndrome (from the Limiting UNdertreatment of lipids in ACS With Rosuvastatin [LUNAR] Trial) Christie M. Ballantyne, MDa,*, Bertram Pitt, MDb, Joseph Loscalzo, MD, PhDc, Valerie A. Cain, MSd, and Joel S. Raichlen, MDe The low-density lipoprotein (LDL) cholesterol goal of <70 mg/dl, recommended for patients with acute coronary syndrome, typically requires intensive therapy with high-dose statins. The secondary goals of nonLhigh-density lipoprotein (non-HDL) cholesterol <100 mg/dl and apolipoprotein B (ApoB) <80 mg/dl have been recommended to reduce excess cardiovascular risk not captured by LDL cholesterol. The present post hoc analysis from the Limiting UNdertreatment of lipids in Acute coronary syndrome with Rosuvastatin (LUNAR) study examined the relation of ApoB with LDL cholesterol and non-HDL cholesterol at baseline and during treatment with intensive statin therapy. The LUNAR participants had acute coronary syndrome and received rosuvastatin 40 mg/day or 20 mg/day or atorvastatin 80 mg/day for 12 weeks. Linear regression analyses were used to compare ApoB, direct LDL cholesterol, and non-HDL cholesterol at baseline and during therapy. Of the 682 patients included in the analysis, 220 had triglycerides ‡200 mg/dl. Linear regression analysis showed that correlation of ApoB and non-HDL cholesterol was stronger than that of ApoB and LDL cholesterol and stronger with statin therapy than at baseline (R2 [ 0.93 for ApoB vs non-HDL cholesterol with statins). The target of ApoB of 80 mg/dl correlated with LDL cholesterol of 90 mg/dl and non-HDL cholesterol of 110 mg/dl at baseline and with LDL cholesterol of 74 mg/dl and non-HDL cholesterol of 92 mg/dl with statin therapy. For high-triglyceride patients, the corresponding on-treatment targets were LDL cholesterol of 68 mg/dl and non-HDL cholesterol of 92 mg/dl. In conclusion, non-HDL cholesterol is an adequate surrogate of ApoB during statin therapy, independent of triglyceride status. However, to match LDL cholesterol and ApoB treatment goals in the very-high-risk category, the current non-HDL cholesterol goal should be lowered by 8 to 10 mg/dl. Ó 2013 Elsevier Inc. All rights reserved. (Am J Cardiol 2013;111:506e509) Patients with acute coronary syndrome (ACS), defined as any constellation of symptoms suggesting acute myocardial ischemia, including myocardial infarction and unstable angina pectoris,1 are at very high risk of adverse cardiovascular outcomes and generally require intensive lipid-lowering therapy to achieve adequate risk reduction.2,3 For this patient population, both the American Diabetes Association/American College of Cardiology and European Society of Cardiology/European Atherosclerosis Society guidelines on lipid management recommend low-density lipoprotein a Baylor College of Medicine and Methodist DeBakey Heart and Vascular Center, Houston, Texas; bDepartment of Internal Medicine, University of Michigan, Ann Arbor, Michigan; cBrigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts; dDepartments of Biostatistics and eClinical Development, AstraZeneca, Wilmington, Delaware. Manuscript received August 7, 2012; revised manuscript received and accepted October 22, 2012. LUNAR was supported by AstraZeneca Pharmaceuticals LP (Wilmington, Delaware); editorial assistance, funded by AstraZeneca Pharmaceuticals LP, was provided by Scientific Connexions (Newtown, Pennsylvania). See page 509 for disclosure information. *Corresponding author: Tel: (713) 798-5034; fax: (713) 798-3057. E-mail address: [email protected] (C.M. Ballantyne).
0002-9149/12/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2012.10.037
(LDL) cholesterol <70 mg/dl as the primary treatment target, with nonehigh-density lipoprotein (non-HDL) cholesterol <100 mg/dl and apolipoprotein B (ApoB) <80 mg/dl as secondary targets.3,4 Although the targets for stable patients with coronary artery disease are LDL cholesterol <100 mg/dl, non-HDL cholesterol <130 mg/dl, and ApoB <90 or <100 mg/dl, ACS requires more intensive therapy to achieve adequate risk reduction. The present post hoc analysis of data from the Limiting UNdertreatment of lipids in ACS with Rosuvastatin (LUNAR) trial5,6 examined how intensive statin therapy in patients with ACS affects the relations between ApoB and LDL cholesterol and between ApoB and non-HDL cholesterol. Specifically, the present analysis sought to determine the LDL cholesterol and nonHDL cholesterol levels in patients with ACS receiving highdose statin therapy that would have to be achieved to meet ApoB targets of 80 mg/dl or 90 mg/dl. Methods The LUNAR trial was a prospective, multicenter (169 sites), randomized, open-label, 3-arm, parallel-group phase IIIb study (AstraZeneca study D3560L00021 [4522US/ 0001]; www.clinicaltrials.gov identifier NCT00214630). www.ajconline.org
Coronary Artery Disease/Intensive Statins, ApoB, Non-HDL Cholesterol in ACS
507
The study design and patient selection criteria have been previously reported.5,6 In brief, LUNAR participants were men and women aged 18 to 75 years with LDL cholesterol >70 mg/dl and fasting triglycerides (TG) <500 mg/dl who had been hospitalized for ACS within 48 hours after the initial symptoms. Eligible patients had unstable angina pectoris, had ST-segment elevation myocardial infarction but underwent successful reperfusion therapy within 12 hours after symptom onset, or had noneSTsegment elevation myocardial infarction. Patients received rosuvastatin 20 mg/day, rosuvastatin 40 mg/day, or atorvastatin 80 mg/day for 12 weeks. Baseline lipids were measured after the patients had fasted overnight. Lipid levels during therapy were measured 6 and 12 weeks after the initiation of statin therapy. Onstatin lipid values represented the average of 2 measurements at weeks 6 and 12. Serum levels of LDL cholesterol were measured using the Direct LDL-C Plus process. The distribution of values of LDL cholesterol and non-HDL cholesterol as a function of ApoB levels was examined before and after statin therapy, with a focus on the average values necessary to achieve the specific target levels of ApoB. The associations between lipid parameters and ApoB were assessed by linear regression analysis for all evaluable patients and for subgroups defined by normal (<200 mg/dl) and high (200 mg/dl) baseline TG values.
aged <65 years (Table 1). Obesity, defined as a body mass index >30 kg/m2, was common (41%). Approximately 1/3 of the evaluable patients (32.3%) had a baseline TG level of 200 mg/dl. The mean baseline values for direct LDL cholesterol, non-HDL cholesterol, and ApoB were 140.9, 166.8, and 128.6 mg/dl, respectively. Figures 1 and 2 show the results of regression analyses examining the relation of ApoB to direct LDL cholesterol and non-HDL cholesterol at baseline and during statin therapy. The correlation of ApoB with LDL cholesterol at baseline (R2 ¼ 0.79; Figure 1) was strengthened by statin therapy (R2 ¼ 0.86; Figure 1). Similarly, the correlation of ApoB with non-HDL cholesterol at baseline (R2 ¼ 0.85; Figure 2) was strengthened by statin therapy (R2 ¼ 0.93; Figure 2). The correlation of ApoB with non-HDL cholesterol was stronger than that with LDL cholesterol, both at baseline and during statin therapy, with the strongest correlation observed for the on-statin values of ApoB and non-HDL cholesterol (Figures 1 and 2). According to the regression analyses, an ApoB value of 90 mg/dl correlated with an LDL cholesterol value of 101 mg/dl at baseline and with an LDL cholesterol value of 85 mg/dl during statin therapy (Table 2). The ApoB value of 80 mg/dl corresponded to LDL cholesterol values of 90 mg/dl at baseline and 74 mg/dl with statin therapy in the analysis population. Thus, the analysis predicts that patients with ACS who achieved their primary goal of LDL cholesterol <70 mg/dl with intensive statin therapy on average would also meet the secondary ApoB goal of <80 mg/dl. Regression analyses of ApoB and non-HDL cholesterol showed that an ApoB value of 90 mg/dl correlated with a nonHDL cholesterol value of 122 mg/dl at baseline and with a non-HDL cholesterol value of 105 mg/dl with statin therapy (Table 3). The ApoB value of 80 mg/dl correlated with nonHDL cholesterol values of 110 mg/dl at baseline and 92 mg/dl with statin therapy. From this analysis, the secondary ApoB goal of <80 mg/dl was found to be more stringent than the secondary non-HDL cholesterol goal of <100 mg/dl. Stratification of the correlation analyses by TG status showed that both at baseline and during therapy, the LDL cholesterol values that correlated with the secondary ApoB targets were consistently lower among patients with high TG than they were among patients with normal TG (Table 2). An on-statin therapy ApoB level of 80 mg/dl correlated with LDL cholesterol values of 68 mg/dl and 77 mg/dl in highTG and normal-TG patients, respectively. In contrast, the non-HDL cholesterol values that correlated with specific ApoB targets at baseline were greater among the high-TG than among the normal-TG patients (Table 3). The on-statin correlation of ApoB versus non-HDL cholesterol was high and showed no substantial differences between high-TG and normal-TG patients in R2 values or in non-HDL cholesterol values correlated with ApoB targets (Table 3).
Results
Discussion
Of the 825 patients with ACS randomized for statin treatment, 682 (82.7%) had evaluable ApoB, non-HDL cholesterol, and direct LDL cholesterol values available at baseline and after 6 and/or 12 weeks of statin therapy. Of those, most were men, most were white, and most were
Patients with ACS belong in the category of individuals at very high risk of cardiovascular events.2,3 The results of our linear regression analyses confirm previous observations that statin therapy alters the relation between ApoB and lipid parameters7,8 and suggest a good concordance
Table 1 Patient baseline characteristics Characteristic Age (yrs) <65 yrs Gender Women Men Race White Black Hispanic Asian Other Body mass index (kg/m2) 30 kg/m2 Acute coronary syndrome ST-segment elevation myocardial infarction NoneST-segment elevation myocardial infarction Unstable angina pectoris Triglycerides 200 mg/dl Baseline lipid values (mg/dl) Low-density lipoprotein cholesterol Nonehigh-density lipoprotein cholesterol Apolipoprotein B High-density lipoprotein cholesterol
Patients (n ¼ 682) 53.2 9.1 603 (88%) 163 (24%) 519 (76%) 553 (81%) 79 (12%) 33 (5%) 3 (0.4%) 14 (2%) 30.1 5.8 280 (41%) 264 245 173 220
(39%) (36%) (25%) (32.3%)
140.9 33.1 166.8 35.6 128.6 28.3 39.8 10.0
Data are presented as mean SD or n (%).
508
The American Journal of Cardiology (www.ajconline.org)
Figure 1. Relation between ApoB and LDL cholesterol at baseline and during statin therapy in patients with acute coronary syndrome. (A) Patients at baseline (untreated). (B) Same patients during statin therapy. ATV80 ¼ atorvastatin 80 mg; RSV20 ¼ rosuvastatin 20 mg; RSV40 ¼ rosuvastatin 40 mg.
Figure 2. Relation between ApoB and non-HDL cholesterol at baseline and during statin therapy in patients with acute coronary syndrome. (A) Patients at baseline (untreated). (B) Same patients during statin therapy. ATV80 ¼ atorvastatin 80 mg; RSV20 ¼ rosuvastatin 20 mg; RSV40 ¼ rosuvastatin 40 mg.
between the currently recommended primary (LDL cholesterol <70 mg/dl) and secondary (ApoB <80 mg/dl) treatment goals for patients with ACS on statin therapy. The LDL cholesterol goal of <70 mg/dl is largely equivalent to the ApoB goal of <80 mg/dl; however, to meet this goal, patients with ACS with high baseline TG levels need to achieve LDL cholesterol values approximately 10 mg/dl less than those required for patients with normal TG values. Our data also suggest that non-HDL cholesterol <100 mg/dl is a less stringent target than LDL cholesterol <70 mg/dl for this patient population because meeting the ApoB goal of 80 mg/dl would require achieving a non-HDL cholesterol value of 92 mg/dl. Non-HDL cholesterol showed a stronger correlation with ApoB than LDL cholesterol and was not affected by TG status. Compared with the results of the Measuring Effective Reductions in Cholesterol Using Rosuvastatin therapY (MERCURY) II study, which examined patients with high coronary heart disease risk treated with lower statin dosages, those of our regression analyses were remarkably similar. As in MERCURY II,8 on-statin linear regression of ApoB
versus non-HDL cholesterol was associated with coefficients of determination (R2) of 0.92 or 0.93, irrespective of TG status. These values suggest a tight correlation between ApoB and non-HDL cholesterol. In addition, the non-HDL cholesterol values that correlated with ApoB of 90 mg/dl, the treatment goal suggested by American Diabetes Association/American College of Cardiology,4 were virtually identical in both studies (i.e., 104 mg/dl or 105 mg/dl).8 These findings suggest that non-HDL cholesterol is a reliable surrogate of ApoB for high-risk patients receiving statin therapy and should be considered a valid alternative measure of overall atherogenic burden. The results of our study have also confirmed that ApoB <90 mg/dl is an aggressive treatment goal that might not be met by many high-risk patients who achieve the currently recommended LDL cholesterol or non-HDL cholesterol targets of 100 mg/dl and 130 mg/dl, respectively. To achieve the more aggressive goal of ApoB <80 mg/dl with statin therapy, the goal of LDL cholesterol <70 mg/dl would suffice; however, the non-HDL cholesterol target
Coronary Artery Disease/Intensive Statins, ApoB, Non-HDL Cholesterol in ACS Table 2 Linear regression of apolipoprotein B (ApoB) versus low-density lipoprotein (LDL) cholesterol at baseline and during statin therapy for patients with acute coronary syndrome Triglycerides (mg/dl)
Patients Slope Intercept R2 (n)
LDL Cholesterol (mg/dl)* ApoB ApoB 90 mg/dl 80 mg/dl
Baseline <200 200 All patients During statin therapy <200 200 All patients
462 220 682
1.12 1.03 1.04
0.4 þ2.0 þ6.6
0.83 0.75 0.79
100.7 95.1 100.5
89.5 84.7 90.1
462 220 682
1.17 1.06 1.09
16.9 16.1 13.6
0.89 0.88 0.86
88.5 79.0 84.9
76.8 68.4 73.9
* Direct measurement. Table 3 Linear regression of apolipoprotein B (ApoB) versus nonehigh-density lipoprotein (non-HDL) cholesterol at baseline and during statin therapy in patients with acute coronary syndrome Triglycerides (mg/dl)
Patients Slope Intercept R2 (n)
Non-HDL Cholesterol ApoB ApoB 90 mg/dl 80 mg/dl
Baseline <200 200 All patients During statin therapy <200 200 All patients
462 220 682
1.18 1.08 1.16
þ14.3 þ30.5 þ17.8
0.85 0.80 0.85
120.5 127.8 122.0
108.7 117.0 110.4
462 220 682
1.28 1.24 1.26
10.0 7.1 8.7
0.93 0.92 0.93
105.2 104.1 104.7
92.4 91.7 92.1
required would be closer to 90 mg/dl. The benefit of this lower targeted goal warrants examination in clinical outcomes trials that monitor non-HDL cholesterol levels and cardiovascular events. Such studies could provide insight regarding the relative value of altering LDL cholesterol versus non-HDL cholesterol and ApoB in the prediction of cardiovascular outcomes in high-risk patients. Disclosures Dr. Ballantyne has received grant/research support (all paid to the institution, not the individual) from Abbott (Abbott Park, Illinois), Amarin (Bedminster, New Jersey), AstraZeneca (Wilmington, Delaware), Bristol-Myers Squibb (New York, New York), GlaxoSmithKline (Research Triangle Park, North Carolina), Genentech (South San Francisco, California), Kowa (Montgomery, Alabama), Merck (Whitehouse Station, New Jersey), Novartis (East Hanover, New Jersey), Roche (Basel, Switzerland), Sanofi-Synthelabo (Paris, France), Takeda (San Diego, California), National Institutes of Health (Bethesda, Maryland), American Diabetes Association (Alexandria, Virginia), and American Heart Association
509
(Dallas, Texas); has served as a consultant for Abbott, Adnexus (Waltham, Massachusetts), Amarin, Amylin (San Diego, California), AstraZeneca, Bristol-Myers Squibb, Esperion (Plymouth, Michigan), Genentech, GlaxoSmithKline, Idera Pharma (Cambridge, Massachusetts), Kowa, Merck, Novartis, Omthera (Princeton, New Jersey), Pfizer (New York, New York), Resverlogix (San Francisco, California), Roche, Sanofi-Synthelabo, and Takeda; has served on the speakers bureau for Abbott, GlaxoSmithKline, and Merck; and has received honoraria from Abbott, Adnexus, Amarin, Amylin, AstraZeneca, Bristol-Myers Squibb, Esperion, Genentech, GlaxoSmithKline, Idera Pharma, Kowa, Merck, Novartis, Omthera, Resverlogix, Roche, Sanofi-Synthelabo, and Takeda. Dr. Pitt had served as a consultant to AstraZeneca, Merck, Novartis, Pfizer, Bayer (Pittsburgh, Pennsylvania), Boehringer Ingelheim (Ridgefield, Connecticut), Forest Laboratories (New York, New York), and Takeda. Dr. Loscalzo has served on the Scientific Advisory Committee of the LUNAR Trial as a paid consultant. Ms. Cain and Dr. Raichlen are employees of AstraZeneca. 1. Anderson JL, Adams CD, Antman EM, Bridges CR, Califf RM, Casey DE Jr, Chavey WE II, Fesmire FM, Hochman JS, Levin TN, Lincoff AM, Peterson ED, Theroux P, Wenger NK, Wright RS. ACC/ AHA 2007 guidelines for the management of patients with unstable angina/non ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction). Developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons: endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. Circulation 2007;116:e148ee304. 2. 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. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110:227e239. 3. Task Force for the Management of Dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS); Reiner Z, Catapano AL, De Backer G, Graham I, Taskinen MR, Wiklund O, Agewall S, Alegria E, Chapman MJ, Durrington P, Erdine S, Halcox J, Hobbs R, Kjekshus J, Filardi PP, Riccardi G, Storey RF, Wood D. ESC/EAS guidelines for the management of dyslipidaemias. Eur Heart J 2011;32:1769e1818. 4. Brunzell JD, Davidson M, Furberg CD, Goldberg RB, Howard BV, Stein JH, Witztum JL. Lipoprotein management in patients with cardiometabolic risk: consensus conference report from the American Diabetes Association and the American College of Cardiology Foundation. J Am Coll Cardiol 2008;51:1512e1524. 5. Pitt B, Loscalzo J, Ycas J, Raichlen JS. Lipid levels after acute coronary syndromes. J Am Coll Cardiol 2008;51:1440e1445. 6. Pitt B, Loscalzo J, Monyak J, Miller M, Raichlen J. Comparison of lipid-modifying efficacy of rosuvastatin versus atorvastatin in patients with acute coronary syndrome (from the LUNAR study). Am J Cardiol 2012;109:1239e1246. 7. Sniderman AD, Furberg CD, Keech A, Roeters van Lennep JE, Frohlich J, Jungner I, Walldius G. Apolipoproteins versus lipids as indices of coronary risk and as targets for statin treatment. Lancet 2003;361:777e780. 8. Ballantyne CM, Raichlen JS, Cain VA. Statin therapy alters the relationship between apolipoprotein B and low-density lipoprotein cholesterol and nonhigh-density lipoprotein cholesterol targets in high-risk patients: the MERCURY II (Measuring Effective Reductions in Cholesterol Using Rosuvastatin therapY) trial. J Am Coll Cardiol 2008;52:626e632.
0002-9149/12/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2012.10.037
(LDL) cholesterol <70 mg/dl as the primary treatment target, with nonehigh-density lipoprotein (non-HDL) cholesterol <100 mg/dl and apolipoprotein B (ApoB) <80 mg/dl as secondary targets.3,4 Although the targets for stable patients with coronary artery disease are LDL cholesterol <100 mg/dl, non-HDL cholesterol <130 mg/dl, and ApoB <90 or <100 mg/dl, ACS requires more intensive therapy to achieve adequate risk reduction. The present post hoc analysis of data from the Limiting UNdertreatment of lipids in ACS with Rosuvastatin (LUNAR) trial5,6 examined how intensive statin therapy in patients with ACS affects the relations between ApoB and LDL cholesterol and between ApoB and non-HDL cholesterol. Specifically, the present analysis sought to determine the LDL cholesterol and nonHDL cholesterol levels in patients with ACS receiving highdose statin therapy that would have to be achieved to meet ApoB targets of 80 mg/dl or 90 mg/dl. Methods The LUNAR trial was a prospective, multicenter (169 sites), randomized, open-label, 3-arm, parallel-group phase IIIb study (AstraZeneca study D3560L00021 [4522US/ 0001]; www.clinicaltrials.gov identifier NCT00214630). www.ajconline.org
Coronary Artery Disease/Intensive Statins, ApoB, Non-HDL Cholesterol in ACS
507
The study design and patient selection criteria have been previously reported.5,6 In brief, LUNAR participants were men and women aged 18 to 75 years with LDL cholesterol >70 mg/dl and fasting triglycerides (TG) <500 mg/dl who had been hospitalized for ACS within 48 hours after the initial symptoms. Eligible patients had unstable angina pectoris, had ST-segment elevation myocardial infarction but underwent successful reperfusion therapy within 12 hours after symptom onset, or had noneSTsegment elevation myocardial infarction. Patients received rosuvastatin 20 mg/day, rosuvastatin 40 mg/day, or atorvastatin 80 mg/day for 12 weeks. Baseline lipids were measured after the patients had fasted overnight. Lipid levels during therapy were measured 6 and 12 weeks after the initiation of statin therapy. Onstatin lipid values represented the average of 2 measurements at weeks 6 and 12. Serum levels of LDL cholesterol were measured using the Direct LDL-C Plus process. The distribution of values of LDL cholesterol and non-HDL cholesterol as a function of ApoB levels was examined before and after statin therapy, with a focus on the average values necessary to achieve the specific target levels of ApoB. The associations between lipid parameters and ApoB were assessed by linear regression analysis for all evaluable patients and for subgroups defined by normal (<200 mg/dl) and high (200 mg/dl) baseline TG values.
aged <65 years (Table 1). Obesity, defined as a body mass index >30 kg/m2, was common (41%). Approximately 1/3 of the evaluable patients (32.3%) had a baseline TG level of 200 mg/dl. The mean baseline values for direct LDL cholesterol, non-HDL cholesterol, and ApoB were 140.9, 166.8, and 128.6 mg/dl, respectively. Figures 1 and 2 show the results of regression analyses examining the relation of ApoB to direct LDL cholesterol and non-HDL cholesterol at baseline and during statin therapy. The correlation of ApoB with LDL cholesterol at baseline (R2 ¼ 0.79; Figure 1) was strengthened by statin therapy (R2 ¼ 0.86; Figure 1). Similarly, the correlation of ApoB with non-HDL cholesterol at baseline (R2 ¼ 0.85; Figure 2) was strengthened by statin therapy (R2 ¼ 0.93; Figure 2). The correlation of ApoB with non-HDL cholesterol was stronger than that with LDL cholesterol, both at baseline and during statin therapy, with the strongest correlation observed for the on-statin values of ApoB and non-HDL cholesterol (Figures 1 and 2). According to the regression analyses, an ApoB value of 90 mg/dl correlated with an LDL cholesterol value of 101 mg/dl at baseline and with an LDL cholesterol value of 85 mg/dl during statin therapy (Table 2). The ApoB value of 80 mg/dl corresponded to LDL cholesterol values of 90 mg/dl at baseline and 74 mg/dl with statin therapy in the analysis population. Thus, the analysis predicts that patients with ACS who achieved their primary goal of LDL cholesterol <70 mg/dl with intensive statin therapy on average would also meet the secondary ApoB goal of <80 mg/dl. Regression analyses of ApoB and non-HDL cholesterol showed that an ApoB value of 90 mg/dl correlated with a nonHDL cholesterol value of 122 mg/dl at baseline and with a non-HDL cholesterol value of 105 mg/dl with statin therapy (Table 3). The ApoB value of 80 mg/dl correlated with nonHDL cholesterol values of 110 mg/dl at baseline and 92 mg/dl with statin therapy. From this analysis, the secondary ApoB goal of <80 mg/dl was found to be more stringent than the secondary non-HDL cholesterol goal of <100 mg/dl. Stratification of the correlation analyses by TG status showed that both at baseline and during therapy, the LDL cholesterol values that correlated with the secondary ApoB targets were consistently lower among patients with high TG than they were among patients with normal TG (Table 2). An on-statin therapy ApoB level of 80 mg/dl correlated with LDL cholesterol values of 68 mg/dl and 77 mg/dl in highTG and normal-TG patients, respectively. In contrast, the non-HDL cholesterol values that correlated with specific ApoB targets at baseline were greater among the high-TG than among the normal-TG patients (Table 3). The on-statin correlation of ApoB versus non-HDL cholesterol was high and showed no substantial differences between high-TG and normal-TG patients in R2 values or in non-HDL cholesterol values correlated with ApoB targets (Table 3).
Results
Discussion
Of the 825 patients with ACS randomized for statin treatment, 682 (82.7%) had evaluable ApoB, non-HDL cholesterol, and direct LDL cholesterol values available at baseline and after 6 and/or 12 weeks of statin therapy. Of those, most were men, most were white, and most were
Patients with ACS belong in the category of individuals at very high risk of cardiovascular events.2,3 The results of our linear regression analyses confirm previous observations that statin therapy alters the relation between ApoB and lipid parameters7,8 and suggest a good concordance
Table 1 Patient baseline characteristics Characteristic Age (yrs) <65 yrs Gender Women Men Race White Black Hispanic Asian Other Body mass index (kg/m2) 30 kg/m2 Acute coronary syndrome ST-segment elevation myocardial infarction NoneST-segment elevation myocardial infarction Unstable angina pectoris Triglycerides 200 mg/dl Baseline lipid values (mg/dl) Low-density lipoprotein cholesterol Nonehigh-density lipoprotein cholesterol Apolipoprotein B High-density lipoprotein cholesterol
Patients (n ¼ 682) 53.2 9.1 603 (88%) 163 (24%) 519 (76%) 553 (81%) 79 (12%) 33 (5%) 3 (0.4%) 14 (2%) 30.1 5.8 280 (41%) 264 245 173 220
(39%) (36%) (25%) (32.3%)
140.9 33.1 166.8 35.6 128.6 28.3 39.8 10.0
Data are presented as mean SD or n (%).
508
The American Journal of Cardiology (www.ajconline.org)
Figure 1. Relation between ApoB and LDL cholesterol at baseline and during statin therapy in patients with acute coronary syndrome. (A) Patients at baseline (untreated). (B) Same patients during statin therapy. ATV80 ¼ atorvastatin 80 mg; RSV20 ¼ rosuvastatin 20 mg; RSV40 ¼ rosuvastatin 40 mg.
Figure 2. Relation between ApoB and non-HDL cholesterol at baseline and during statin therapy in patients with acute coronary syndrome. (A) Patients at baseline (untreated). (B) Same patients during statin therapy. ATV80 ¼ atorvastatin 80 mg; RSV20 ¼ rosuvastatin 20 mg; RSV40 ¼ rosuvastatin 40 mg.
between the currently recommended primary (LDL cholesterol <70 mg/dl) and secondary (ApoB <80 mg/dl) treatment goals for patients with ACS on statin therapy. The LDL cholesterol goal of <70 mg/dl is largely equivalent to the ApoB goal of <80 mg/dl; however, to meet this goal, patients with ACS with high baseline TG levels need to achieve LDL cholesterol values approximately 10 mg/dl less than those required for patients with normal TG values. Our data also suggest that non-HDL cholesterol <100 mg/dl is a less stringent target than LDL cholesterol <70 mg/dl for this patient population because meeting the ApoB goal of 80 mg/dl would require achieving a non-HDL cholesterol value of 92 mg/dl. Non-HDL cholesterol showed a stronger correlation with ApoB than LDL cholesterol and was not affected by TG status. Compared with the results of the Measuring Effective Reductions in Cholesterol Using Rosuvastatin therapY (MERCURY) II study, which examined patients with high coronary heart disease risk treated with lower statin dosages, those of our regression analyses were remarkably similar. As in MERCURY II,8 on-statin linear regression of ApoB
versus non-HDL cholesterol was associated with coefficients of determination (R2) of 0.92 or 0.93, irrespective of TG status. These values suggest a tight correlation between ApoB and non-HDL cholesterol. In addition, the non-HDL cholesterol values that correlated with ApoB of 90 mg/dl, the treatment goal suggested by American Diabetes Association/American College of Cardiology,4 were virtually identical in both studies (i.e., 104 mg/dl or 105 mg/dl).8 These findings suggest that non-HDL cholesterol is a reliable surrogate of ApoB for high-risk patients receiving statin therapy and should be considered a valid alternative measure of overall atherogenic burden. The results of our study have also confirmed that ApoB <90 mg/dl is an aggressive treatment goal that might not be met by many high-risk patients who achieve the currently recommended LDL cholesterol or non-HDL cholesterol targets of 100 mg/dl and 130 mg/dl, respectively. To achieve the more aggressive goal of ApoB <80 mg/dl with statin therapy, the goal of LDL cholesterol <70 mg/dl would suffice; however, the non-HDL cholesterol target
Coronary Artery Disease/Intensive Statins, ApoB, Non-HDL Cholesterol in ACS Table 2 Linear regression of apolipoprotein B (ApoB) versus low-density lipoprotein (LDL) cholesterol at baseline and during statin therapy for patients with acute coronary syndrome Triglycerides (mg/dl)
Patients Slope Intercept R2 (n)
LDL Cholesterol (mg/dl)* ApoB ApoB 90 mg/dl 80 mg/dl
Baseline <200 200 All patients During statin therapy <200 200 All patients
462 220 682
1.12 1.03 1.04
0.4 þ2.0 þ6.6
0.83 0.75 0.79
100.7 95.1 100.5
89.5 84.7 90.1
462 220 682
1.17 1.06 1.09
16.9 16.1 13.6
0.89 0.88 0.86
88.5 79.0 84.9
76.8 68.4 73.9
* Direct measurement. Table 3 Linear regression of apolipoprotein B (ApoB) versus nonehigh-density lipoprotein (non-HDL) cholesterol at baseline and during statin therapy in patients with acute coronary syndrome Triglycerides (mg/dl)
Patients Slope Intercept R2 (n)
Non-HDL Cholesterol ApoB ApoB 90 mg/dl 80 mg/dl
Baseline <200 200 All patients During statin therapy <200 200 All patients
462 220 682
1.18 1.08 1.16
þ14.3 þ30.5 þ17.8
0.85 0.80 0.85
120.5 127.8 122.0
108.7 117.0 110.4
462 220 682
1.28 1.24 1.26
10.0 7.1 8.7
0.93 0.92 0.93
105.2 104.1 104.7
92.4 91.7 92.1
required would be closer to 90 mg/dl. The benefit of this lower targeted goal warrants examination in clinical outcomes trials that monitor non-HDL cholesterol levels and cardiovascular events. Such studies could provide insight regarding the relative value of altering LDL cholesterol versus non-HDL cholesterol and ApoB in the prediction of cardiovascular outcomes in high-risk patients. Disclosures Dr. Ballantyne has received grant/research support (all paid to the institution, not the individual) from Abbott (Abbott Park, Illinois), Amarin (Bedminster, New Jersey), AstraZeneca (Wilmington, Delaware), Bristol-Myers Squibb (New York, New York), GlaxoSmithKline (Research Triangle Park, North Carolina), Genentech (South San Francisco, California), Kowa (Montgomery, Alabama), Merck (Whitehouse Station, New Jersey), Novartis (East Hanover, New Jersey), Roche (Basel, Switzerland), Sanofi-Synthelabo (Paris, France), Takeda (San Diego, California), National Institutes of Health (Bethesda, Maryland), American Diabetes Association (Alexandria, Virginia), and American Heart Association
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(Dallas, Texas); has served as a consultant for Abbott, Adnexus (Waltham, Massachusetts), Amarin, Amylin (San Diego, California), AstraZeneca, Bristol-Myers Squibb, Esperion (Plymouth, Michigan), Genentech, GlaxoSmithKline, Idera Pharma (Cambridge, Massachusetts), Kowa, Merck, Novartis, Omthera (Princeton, New Jersey), Pfizer (New York, New York), Resverlogix (San Francisco, California), Roche, Sanofi-Synthelabo, and Takeda; has served on the speakers bureau for Abbott, GlaxoSmithKline, and Merck; and has received honoraria from Abbott, Adnexus, Amarin, Amylin, AstraZeneca, Bristol-Myers Squibb, Esperion, Genentech, GlaxoSmithKline, Idera Pharma, Kowa, Merck, Novartis, Omthera, Resverlogix, Roche, Sanofi-Synthelabo, and Takeda. Dr. Pitt had served as a consultant to AstraZeneca, Merck, Novartis, Pfizer, Bayer (Pittsburgh, Pennsylvania), Boehringer Ingelheim (Ridgefield, Connecticut), Forest Laboratories (New York, New York), and Takeda. Dr. Loscalzo has served on the Scientific Advisory Committee of the LUNAR Trial as a paid consultant. Ms. Cain and Dr. Raichlen are employees of AstraZeneca. 1. Anderson JL, Adams CD, Antman EM, Bridges CR, Califf RM, Casey DE Jr, Chavey WE II, Fesmire FM, Hochman JS, Levin TN, Lincoff AM, Peterson ED, Theroux P, Wenger NK, Wright RS. ACC/ AHA 2007 guidelines for the management of patients with unstable angina/non ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction). Developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons: endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. Circulation 2007;116:e148ee304. 2. 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. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110:227e239. 3. Task Force for the Management of Dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS); Reiner Z, Catapano AL, De Backer G, Graham I, Taskinen MR, Wiklund O, Agewall S, Alegria E, Chapman MJ, Durrington P, Erdine S, Halcox J, Hobbs R, Kjekshus J, Filardi PP, Riccardi G, Storey RF, Wood D. ESC/EAS guidelines for the management of dyslipidaemias. Eur Heart J 2011;32:1769e1818. 4. Brunzell JD, Davidson M, Furberg CD, Goldberg RB, Howard BV, Stein JH, Witztum JL. Lipoprotein management in patients with cardiometabolic risk: consensus conference report from the American Diabetes Association and the American College of Cardiology Foundation. J Am Coll Cardiol 2008;51:1512e1524. 5. Pitt B, Loscalzo J, Ycas J, Raichlen JS. Lipid levels after acute coronary syndromes. J Am Coll Cardiol 2008;51:1440e1445. 6. Pitt B, Loscalzo J, Monyak J, Miller M, Raichlen J. Comparison of lipid-modifying efficacy of rosuvastatin versus atorvastatin in patients with acute coronary syndrome (from the LUNAR study). Am J Cardiol 2012;109:1239e1246. 7. Sniderman AD, Furberg CD, Keech A, Roeters van Lennep JE, Frohlich J, Jungner I, Walldius G. Apolipoproteins versus lipids as indices of coronary risk and as targets for statin treatment. Lancet 2003;361:777e780. 8. Ballantyne CM, Raichlen JS, Cain VA. Statin therapy alters the relationship between apolipoprotein B and low-density lipoprotein cholesterol and nonhigh-density lipoprotein cholesterol targets in high-risk patients: the MERCURY II (Measuring Effective Reductions in Cholesterol Using Rosuvastatin therapY) trial. J Am Coll Cardiol 2008;52:626e632.