A 67 year-old man with coronary artery disease, hypertension, obesity, and diabetes mellitus presents to your office for follow-up after a recent hospitalization during which he underwent percutaneous coronary intervention for unstable angina two weeks ago. He underwent coronary artery bypass surgery for unstable angina in 2007 with LIMA-LAD, RIMA-RCA, and SVG-obtuse marginal grafts. During his recent hospitalization, he received a drug eluting stent to his native Ramus Intermedius branch with resolution of his chest discomfort. He is without complaints on this visit.
He has a six pack-year smoking history, which he quit in 1970. He drinks a glass of wine nightly. He continues to exercise on a treadmill at a brisk pace for 30 minutes, five times a week, as he was doing before his recent hospitalization. He is trying to follow a Mediterranean diet plan with the hopes of losing weight.
His blood pressure is 128/80, pulse is 64, BMI is 28, and waist circumference is 41 inches. His exam is otherwise unremarkable except for a well-healed right femoral access site from his recent catheterization and central adiposity.
His lab work from just prior to this visit shows creatinine 1.2 mg/dL, hemoglobin A1c 6.8%, TC 149 mg/dL, Trig 170 mg/dL, HDL-C 45 mg/dL, LDL-C 70 mg/dl, and apolipoprotein B (apoB) 87 mg/dL.
His medications have included aspirin, metoprolol, lisinopril, metformin and atorvastatin 80 mg daily for several years with the addition of clopidogrel after his recent PCI. He reports full adherence to his medical regimen.
In addition to weight loss and referral to cardiac rehabilitation, he asks what he can do to try to improve his risk.
The correct answer is: D) Any of the above are reasonable approaches.
This high-risk statin-treated patient is an example of the residual risk that we see in everyday practice. One key aspect to consider is the discordance between his lipid values. Long-term, high-potency statin therapy has reduced his LDL-C and non HDL-C to acceptable levels (per ATP III guidelines).1 Despite this, he has had a recurrent coronary event. From a population perspective, although his LDL-C places him at the 15th percentile, his non-HDL-C is at the 25th percentile and his apoB is between the 30th and 40th percentile.2,3 This type of discordance is often typical in diabetic subjects or those with features of the metabolic syndrome.4 Furthermore, LDL-C calculations (Friedewald-calculations) at TG levels above 150 mg/dL often underestimate the true LDL-C.5 Considering potential discordance and underestimation, whereas the LDL-C in this case may be reassuring to some, we view it cautiously.
While randomized controlled trial outcomes evidence is presently lacking for lipid-lowering therapies in addition to statin treatment, strong biological and epidemiological data support targeting a lower apoB.6 Atherosclerosis is fundamentally triggered by the retention of atherogenic particles within the arterial wall.7 Every potentially atherogenic particle contains one surface copy of apoB, which confers atherogenicity to the particle. Cholesterol concentrations within apoB-containing particles, most notably LDL-C or non HDL-C, have long been the clinical standard for assessment of risk and therapeutic targets. However, since the cholesterol content within these particles can vary (i.e. small, dense LDLs carry less cholesterol per particle), apoB consistently outperforms these markers of atherogenic particle burden for risk prediction, particularly when there is discordance.8
For patients with atherosclerotic CVD, the 2013 ACC/AHA cholesterol guidelines only specifically recommend high-potency statin therapy (choice A).9,10 These guidelines are best viewed as a starting point for risk discussion and shared decision-making with your patient, which should include the fact that the patient's residual risk is not zero. Importantly, the guidelines adhered to the strictest evidence base for its recommendations (the highest-quality randomized controlled trials [RCTs] only). The new guidelines shifted from targeting cholesterol levels to suggesting a 50% reduction in LDL-C for high risk subjects through high potency statin use. However, the new guidelines do not address changes to therapy in the setting of recurrent events in those who have been on guideline directed therapy for years, such as this patient. Any management beyond the guideline recommendations should be based on the caregiver's best interpretation of the available data.
Since statins more effectively lower LDL-C and non-HDL-C compared with apoB11, the addition of apoB-reducing therapies (choices B and C) are a reasonable consideration for this patient seeking further options to potentially reduce his risk. Ezetimibe and colesevelam are safe medications that lead to further reductions in apoB when added to statins.12,13 Due to more favorable tolerability, we generally use ezetimibe as our first add-on therapy to achieve greater apoB reductions. We eagerly await the results of the ongoing IMPROVE-IT trial (NCT00202878) testing whether the addition of ezetimibe to statin therapy reduces CVD events.14 Bile acid sequestrants have already been proven to effectively reduce CVD as monotherapy15. Recent disappointing results from trials testing the addition of niacin preparations to statin therapy have created doubt over the role of niacin therapy.16,17 However, it is important to recognize that apoB levels were nearly equivalent in the two treatment arms of AIM-HIGH, suggesting a possible etiology for equivalent outcomes.18 Similar to other add-on agents, we view niacin as an apoB-reducing therapy that may still be considered in those with residually elevated apoB on maximal statin therapy.
Based on post-hoc analyses of statin trials, the ACC/ADA statement in 2008 suggested a target apoB of less than 80 mg/dL in high-risk subjects.19 Recent lipid guidelines from the Canadian Cardiovascular Society also suggest an apoB of less than 80 mg/dL for high-risk subjects.20 Others have argued for a lower target apoB since the equivalent percentile in the general population for an LDL-C of 70 corresponds to an apoB of 60 mg/dL.3 In our experience, an apoB target of 60 mg/dL often requires multiple lipid-lowering therapies. Recognizing the difficulty of attaining an apoB <60 mg/dL,21 we reserve consideration of this aggressive target for those at highest risk for recurrent CVD, such as this patient.
In our practice, the patient who is making the appropriate lifestyle modifications and is already on high-potency statin with discordant apoB levels is an ideal candidate for further apoB reduction. We also target apoB more aggressively in subjects with elevated lipoprotein (a) [Lp(a)], a marker that European guidelines and the National Lipid Association consider reasonable to measure in those with high CVD risk or a family history of premature CVD.22,23 Importantly, in contrast to LDL-C (often calculated), worldwide standards are in place for apoB measurements through the WHO and the CDC, helping to ensure credibility and reproducibility of the results.24 We have reduced the cost of an apoB measurement to $20 by incorporating the simple table-top assay into our clinical lab's throughput.
In discussions with our patients, we emphasize the lack of RCT data for both add-on therapy to statins and treating to a target, advise of possible side effects, and help the patient come to a decision that he or she is comfortable with based on our interpretation of sound scientific evidence. In practice, guidelines are the necessary starting point for risk reduction, but further emerging science can help tailor therapy in motivated patients who remain at risk.
Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. J Am Coll Cardiol 2004;44:720-32.
Elshazly MB, Martin SS, Blaha MJ, et al. Non-high-density lipoprotein cholesterol, guideline targets, and population percentiles for secondary prevention in 1.3 million adults: the VLDL-2 study (very large database of lipids). J Am Coll Cardiol 2013;62:1960-5.
Contois JH, McConnell JP, Sethi AA, et al. Apolipoprotein B and cardiovascular disease risk: position statement from the AACC Lipoproteins and Vascular Diseases Division Working Group on Best Practices. Clin Chem 2009;55:407-19.
Kathiresan S, Otvos JD, Sullivan LM, et al. Increased small low-density lipoprotein particle number: a prominent feature of the metabolic syndrome in the Framingham Heart Study. Circulation 2006;113:20-9.
Martin SS, Blaha MJ, Elshazly MB, et al. Friedewald-estimated versus directly measured low-density lipoprotein cholesterol and treatment implications. J Am Coll Cardiol 2013;62:732-9.
Sniderman AD, Furberg CD, Keech A, et al. Apolipoproteins versus lipids as indices of coronary risk and as targets for statin treatment. Lancet 2003;361:777-80.
Tabas I, Williams KJ, Boren J. Subendothelial lipoprotein retention as the initiating process in atherosclerosis: update and therapeutic implications. Circulation 2007;116:1832-44.
Sniderman AD, Islam S, Yusuf S, McQueen MJ. Discordance analysis of apolipoprotein B and non-high density lipoprotein cholesterol as markers of cardiovascular risk in the INTERHEART study. Atherosclerosis 2012;225:444-9.
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].
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].
Ballantyne CM, Pitt B, Loscalzo J, Cain VA, Raichlen JS. 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). Am J Cardiol 2013;111:506-9.
Telford DE, Sutherland BG, Edwards JY, Andrews JD, Barrett PH, Huff MW. The molecular mechanisms underlying the reduction of LDL apoB-100 by ezetimibe plus simvastatin. J Lipid Res 2007;48:699-708.
Knapp HH, Schrott H, Ma P, et al. Efficacy and safety of combination simvastatin and colesevelam in patients with primary hypercholesterolemia. Am J Med 2001;110:352-60.
Cannon CP, Giugliano RP, Blazing MA, et al. Rationale and design of IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial): comparison of ezetimbe/simvastatin versus simvastatin monotherapy on cardiovascular outcomes in patients with acute coronary syndromes. Am Heart J 2008;156:826-32.
The Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in incidence of coronary heart disease. JAMA 1984;251:351-64.
Investigators A-H, Boden WE, Probstfield JL, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 2011;365:2255-67.
Group HTC. HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of ER niacin/laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment. Eur Heart J 2013;34:1279-91.
Al-Hijji M, Martin SS, Joshi PH, Jones SR. Effect of equivalent on-treatment apolipoprotein levels on outcomes (from the AIM-HIGH and HPS2-THRIVE). Am J Cardiol 2013;112:1697-700.
Brunzell JD, Davidson M, Furberg CD, et al. 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;51:1512-24.
Anderson TJ, Gregoire J, Hegele RA, et al. 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.
Harper CR, Jacobson TA. Using apolipoprotein B to manage dyslipidemic patients: time for a change? Mayo Clin Proc 2010;85:440-5.
European Association for Cardiovascular P, Rehabilitation, Reiner Z, et al. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2011;32:1769-818.
Davidson MH, Ballantyne CM, Jacobson TA, et al. Clinical utility of inflammatory markers and advanced lipoprotein testing: advice from an expert panel of lipid specialists. J Clin Lipid 2011;5:338-67.
Marcovina S, Packard CJ. Measurement and meaning of apolipoprotein AI and apolipoprotein B plasma levels. J Intern Med 2006;259:437-46.