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

References

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