Cholesterol Management in a 46-Year-Old Man Following Myocardial Infarction
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A 46-year-old man presents to clinic six months after sustaining an anterior ST-elevation myocardial infarction treated with primary PCI. A single drug-eluting stent was placed to treat the culprit lesion in the proximal left anterior descending artery. Coronary catheterization revealed moderate disease in the mid right coronary artery. Since his last visit, he denies dyspnea, his anginal equivalent, or side effects attributable to statin therapy. He maintains a low-fat, high-fiber diet and exercises on the treadmill 30 minutes every morning.
His past medical history is notable for hypertension and hyperlipidemia. His older brother suffered an MI at age 43 and his father died suddenly in his 50's. His medications include aspirin, clopidogrel, metoprolol, lisinopril, and atorvastatin 80 mg daily. He reports daily compliance with this regimen. While taking prescription niacin many years ago, he reports developing nausea, anorexia, and "liver test abnormalities," resulting in the drug's discontinuation.
On physical examination, his blood pressure is 130/76 mmHg and his pulse is 63 bpm. His BMI is 26 kg/m2 and his cardiovascular examination is unremarkable. Laboratory values are notable for: LDL–C 102 mg/dL, HDL-C 52 mg/dL, triglycerides 126 mg/dL, creatinine 1.1 mg/dL, glucose 98 mg/dL, hemoglobin A1c 5.6%, uric acid 5.1 mg/dL. His untreated lipid profile is not available, and he reports initiating lipid-lowering therapy over 10 years ago.
What is the most appropriate cholesterol-lowering strategy for this patient?
The correct answer is: D) Atorvastatin 80 mg, colesevelam 3.75 g or ezetimibe 10 mg
At this time, based on current evidence and guidelines, the most appropriate cholesterol-lowering strategy is continuing atorvastatin 80 mg daily and initiating colesevelam 3.75 grams or ezetimibe 10 mg daily.
The patient's clinical presentation suggests familial hypercholesterolemia (FH), one of the most commonly inherited disorders with an estimated prevalence of 1 in 300.1 Although his untreated LDL–C is unknown, assuming a 50-55% reduction as demonstrated in prior trials using atorvastatin 80 mg daily indicates a baseline LDL–C exceeding 200 mg/dL. Hypercholesterolemia to this extent coupled with a personal and family history of premature CHD fulfills clinical criteria for FH according to both the Simon Broome and Dutch Lipid Network classification schemes.2
No randomized, controlled trial (RCT) evidence is yet available to clarify the incremental benefits and harms of combination cholesterol-lowering therapy compared with statin treatment alone among patients with FH. In fact, contemporary RCTs of niacin (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes, AIM-HIGH3) and ezetimibe (Improved Reduction of Outcomes: Vytorin Efficacy International Trial, IMPROVE-IT4) specifically excluded patients with elevated LDL–C. As we eagerly await data from PCSK9 inhibitor outcomes studies that may shed light on the optimal management for patients with FH,5, 6 in the absence of RCT data we "follow the trail to the next best external evidence and work from there."7
Indirect evidence supporting bile acid sequestrant (BAS) or ezetimibe add-on therapy for this case can be found from several sources. The landmark Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) trial demonstrated a 16% lower cardiovascular event rate among patients who received atorvastatin 80 mg daily and achieved a mean LDL–C of 62 mg/dL compared with patients who were randomized to pravastatin 40 mg daily and achieved a mean LDL–C of 95 mg/dL.8 Post-hoc analyses of the PROVE-IT trial9 and the Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) trial10 revealed lower cardiovascular event rates among study participants who achieved lower on-treatment LDL–C levels (<60 mg/dL and <50 mg/dL, respectively). While indirect and susceptible to confounding, these findings suggest that achieving an LDL–C far lower than that observed in the patient described in the case above may better address residual risk.
With particular regard to BAS, RCT data from the pre-statin era support a cardioprotective effect in patients with FH. In the primary prevention Lipid Research Clinics Coronary Prevention Trial (LRC-CPT) of patients with FH (baseline LDL–C 205 mg/dL), treatment with cholestyramine was associated with a 20% reduction in LDL–C and a 19% reduction in fatal CHD and nonfatal MI.11 Ileal bypass, a surgical procedure yielding similar but more potent effects on lipid metabolism as chronic BAS therapy, yielded a 38% reduction in LDL–C and a 35% reduction in fatal CHD and nonfatal MI among MI survivors with FH.12
Absent an RCT of combination cholesterol-lowering therapy, arguably the most compelling supporting data that achieving a lower LDL–C confers a lower risk of MI comes from genetic studies completed over the past decade. Genetic studies mimic RCTs in that random segregation of alleles balances confounding factors, thereby permitting unbiased assessment of the effect of variant alleles on cardiovascular outcomes. Genetic studies of rare, low-frequency, and common variants have consistently demonstrated that human genetic variation associated with lower LDL–C levels is associated with a lower risk of CHD and, conversely, variants associated with higher LDL–C levels are also associated with higher risk.13-15 The relationship between LDL–C levels and CHD risk is notably "dose-dependent," that is, variants associated with substantially lower LDL–C levels confer greater reductions in CHD risk.
The use of BAS/ezetimibe-statin combination therapy is consistent with the recently published 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults.16 The guideline highlights the importance of high-intensity statin therapy in the primary prevention of atherosclerotic cardiovascular disease (ASCVD) among individuals 21 years and older with LDL–C>190 mg/dL.16 Recognizing that nonstatin drugs may be "needed to lower LDL–C to acceptable levels,"16 addition of nonstatin drugs to high-intensity statin therapy is provided a class IIb recommendation (level of evidence C) for patients at high-risk after evaluation of the potential for ASCVD risk reduction, adverse effects, drug-drug interactions, and patient preferences. While no specific targets are provided for patients with familial hypercholesterolemia following acute coronary syndrome, the 2013 ACC/AHA Guideline notes that an LDL–C <100 mg/dL was observed in most individuals receiving high-intensity statin therapy in secondary prevention RCTs.16 The 2013 ACC/AHA Guideline did acknowledge that complex lipid disorders in general were beyond the specific scope of the systematic review that served as the evidentiary base.16 Two recently released guidelines specifically addressing FH also acknowledge the potential utility of BAS, ezetimibe, and/or niacin therapy above and beyond high-intensity statin therapy in FH patients.1, 2
Either initiating BAS or ezetimibe would be appropriate in this case. On the one hand, RCT outcome data are available to support BAS (as monotherapy); on the other hand, ezetimibe is better tolerated. Clinical equipoise is reflected in the different approaches taken by two recently published guidelines. The 2013 ACC/AHA Guideline appears to favor BAS, recommending priority "be given to nonstatin cholesterol-lowering drugs shown to reduce ASCVD events in RCTs."16 The 2013 Consensus Statement of the European Atherosclerosis Society on familial hypercholesterolemia prioritizes ezetimibe "in view of few side effects and high compliance."2
Choice A suggests atorvastatin 80 mg as monotherapy (incorrect). No randomized trial evidence has demonstrated a reduction in cardiovascular events with the addition of BAS, niacin, or ezetimibe to atorvastatin 80 mg alone. However, for this high-risk patient with a recent history of acute coronary syndrome, FH, and an LDL–C above 100 mg/dL, an analysis of benefits and risks supports intensifying cholesterol-lowering therapy with colesevelam (Answer B). This is consistent with the 2013 ACC/AHA Guideline as detailed above.
Choice B suggests addition of lomitapide to atorvastatin (incorrect). Lomitapide, an oral inhibitor of microsomal triglyceride transfer protein, is currently approved for the treatment of homozygous familial hypercholesterolemia (HoFH). Diagnosis of HoFH can be challenging given the limitations of available genotyping techniques and the absence of uniform clinical criteria.17 That said, series of HoFH patients generally report untreated total cholesterol levels exceeding 500 mg/dL,2, 17, 18 well above estimated baseline values for the patient presented in this case.
Choice C suggests addition of niacin to atorvastatin (incorrect). The patient's history suggests niacin-associated hepatotoxicity. While insufficient information is provided to establish a causal relationship, re-attempting niacin is a less appropriate strategy compared with adding a bile acid sequestrant. This is consistent with the 2013 ACC/AHA Guideline which recommends assessment of the potential for adverse effects prior to re-initiation of niacin therapy (Class I/B).16 Importantly, the rationale for not pursuing statin-niacin therapy in this case hinges primarily on tolerability and safety concerns rather than issues regarding efficacy. Results from the niacin trials AIM-HIGH3 and Heart Protection Study 2 - Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE)19 cannot be generalized to patients with familial hypercholesterolemia. In these secondary prevention studies, niacin (or niacin/laropiprant) added to statin (+/- ezetimibe) failed to achieve an incremental cardiovascular benefit above and beyond statin (+/- ezetimibe) therapy. However, the baseline LDL–C levels in AIM-HIGH and HPS2-THRIVE were 76 mg/dL and 63 mg/dL, respectively, far lower than the LDL–C achieved in the majority of patients with familial hypercholesterolemia on statin monotherapy. Although results from HPS2-THRIVE are yet to be published in a peer-reviewed journal, preliminary findings presented at ACC Scientific Sessions 2013 suggest a possible cardiovascular benefit of niacin among patients with higher baseline LDL C levels.19
- Goldberg AC, Hopkins PN, Toth PP, Ballantyne CM, Rader DJ, Robinson JG, Daniels SR, Gidding SS, de Ferranti SD, Ito MK, McGowan MP, Moriarty PM, Cromwell WC, Ross JL, Ziajka PE, National Lipid Association Expert Panel on Familial H. Familial hypercholesterolemia: Screening, diagnosis and management of pediatric and adult patients: Clinical guidance from the national lipid association expert panel on familial hypercholesterolemia. J Clin Lipid. 2011;5:S1-8
- Nordestgaard BG, Chapman MJ, Humphries SE, Ginsberg HN, Masana L, Descamps OS, Wiklund O, Hegele RA, Raal FJ, Defesche JC, Wiegman A, Santos RD, Watts GF, Parhofer KG, Hovingh GK, Kovanen PT, Boileau C, Averna M, Boren J, Bruckert E, Catapano AL, Kuivenhoven JA, Pajukanta P, Ray K, Stalenhoef AF, Stroes E, Taskinen MR, Tybjaerg-Hansen A, European Atherosclerosis Society Consensus P. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: Guidance for clinicians to prevent coronary heart disease: Consensus statement of the european atherosclerosis society. Eur Heart J. 2013;34:3478-3490
- Investigators A-H, Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes-Nickens P, Koprowicz K, McBride R, Teo K, Weintraub W. Niacin in patients with low hdl cholesterol levels receiving intensive statin therapy. N Engl J Med 2011;365:2255-2267
- Cannon CP, Giugliano RP, Blazing MA, Harrington RA, Peterson JL, Sisk CM, Strony J, Musliner TA, McCabe CH, Veltri E, Braunwald E, Califf RM, Investigators I-I. 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;156:826-832
- Sanofi/Renegeron. Evaluation of cardiovascular outcomes after an acute coronary syndrome during treatment with alirocumab sar236553 (regn727) (odyssey outcomes). 2013
- Amgen. Further cardiovascular outcomes research with pcsk9 inhibition in subjects with elevated risk (fourier). 2013
- Sackett DL, Rosenberg WM, Gray JA, Haynes RB, Richardson WS. Evidence based medicine: What it is and what it isn't. BMJ. 1996;312:71-72
- Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, Joyal SV, Hill KA, Pfeffer MA, Skene AM, Pravastatin or Atorvastatin E, Infection Therapy-Thrombolysis in Myocardial Infarction I. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350:1495-1504
- Wiviott SD, Cannon CP, Morrow DA, Ray KK, Pfeffer MA, Braunwald E, Investigators PI-T. Can low-density lipoprotein be too low? The safety and efficacy of achieving very low low-density lipoprotein with intensive statin therapy: A prove it-timi 22 substudy. Am Coll Cardiol. 2005;46:1411-14.
- Hsia J, MacFadyen JG, Monyak J, Ridker PM. Cardiovascular event reduction and adverse events among subjects attaining low-density lipoprotein cholesterol <50 mg/dl with rosuvastatin. The jupiter trial (justification for the use of statins in prevention: An intervention trial evaluating rosuvastatin). J Am Coll Cardiol 2011;57:1666-1675
- The lipid research clinics coronary primary prevention trial results. I. Reduction in incidence of coronary heart disease. JAMA. 1984;251:351-364
- Buchwald H, Varco RL, Matts JP, Long JM, Fitch LL, Campbell GS, Pearce MB, Yellin AE, Edmiston WA, Smink RD, Jr., et al. Effect of partial ileal bypass surgery on mortality and morbidity from coronary heart disease in patients with hypercholesterolemia. Report of the program on the surgical control of the hyperlipidemias (posch). N Engl J Med 1990;323:946-955
- Cohen JC, Boerwinkle E, Mosley TH, Jr., Hobbs HH. Sequence variations in pcsk9, low ldl, and protection against coronary heart disease. N Engl J Med 2006;354:1264-1272
- Voight BF, Peloso GM, Orho-Melander M, et al. Plasma hdl cholesterol and risk of myocardial infarction: A mendelian randomisation study. Lancet. 2012;380:572-580
- Ference BA, Yoo W, Alesh I, et al Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease: A mendelian randomization analysis. J Am Coll Cardiol. 2012;60:2631-2639
- Stone NJ, Robinson J, Lichtenstein AH, et al 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiotvascular risk in adults: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;():. doi:10.1016/j.jacc.2013.11.002
- Raal FJ, Santos RD. Homozygous familial hypercholesterolemia: Current perspectives on diagnosis and treatment. Atherosclerosis. 2012;223:262-268
- Kolansky DM, Cuchel M, Clark BJ, Paridon S, McCrindle BW, Wiegers SE, Araujo L, Vohra Y, Defesche JC, Wilson JM, Rader DJ. Longitudinal evaluation and assessment of cardiovascular disease in patients with homozygous familial hypercholesterolemia. Am J Cardiol 2008;102:1438-1443
- Armitage J. Hps2-thrive: Randomized placebo-controlled trial of er niacin and laropiprant in 25,673 patients with pre-existing cardiovascular disease. American College of Cardiology Scientific Sessions. 2013