A 57-year-old Caucasian male with history of hypertension, hyperlipidemia, gastroesophageal reflux disease, and anxiety presents to clinic with several months of fatigue and reduced exercise capacity. He is an active adult who played lacrosse competitively in college, a former Marine Corps officer, and exercises two hours daily at the gym. He follows a Mediterranean diet though he reports increased cheese intake. He is a non-smoker and consumes two alcoholic beverages daily. Family history is significant for premature atherosclerotic cardiovascular disease (ASCVD). His father died of a "heart attack" at age 53 years. His brother suffered a myocardial infarction (MI) and underwent multiple coronary interventions at age 44 years, and then had repeat MI with subsequent coronary bypass surgery at age 49.
Physical examination noted blood pressure 162/94 mmHg with BMI 27.2 kg/m2 and cardiac exam was normal with regular rate and rhythm, normal heart sounds with no murmur, and lungs clear to auscultation bilaterally. Lipid panel revealed total cholesterol 253 mg/dL, LDL-C 186 mg/dL, HDL-C 37 mg/dL, and triglycerides 146 mg/dL. His 10-year ASCVD risk by the Pooled Cohort Equations is 16%. EKG showed normal sinus rhythm with right bundle branch block, and echocardiogram showed normal biventricular function with no valvular abnormalities.
Due to his symptoms of fatigue and reduced exercise capacity, he was referred for exercise nuclear myocardial perfusion imaging. He exercised on the Bruce protocol for 9 minutes and 4 seconds, achieving 10.1 METs, with normal heart rate and blood pressure response. He did not experience chest pain and no ischemic EKG changes were noted. There was normal myocardial perfusion, normal myocardial thickening and wall motion, and normal left ventricular ejection fraction of 65%. However, he was noted to have extensive subclinical atherosclerosis with multivessel coronary artery calcification (Agatston score 1315, 98th percentile for age and race matched group).
Therapy was initiated with ramipril 10 mg daily, atorvastatin 40mg daily, and he continued previous medications which included aspirin 81mg daily, fish oil supplements, and multivitamin. At 3 month follow-up visit, blood pressure improved to 124/66 mmHg. However, the patient complained of myalgias in his arms and legs limiting his ability to exercise and climb stairs. Repeat lipid panel showed total cholesterol 186 mg/dL, LDL-C 121 mg/dL, HDL-C 40 mg/dL, and triglycerides 125 mg/dL.
Which of the following is the next best step in the management of this patient?
The correct answer is: D. Switch to rosuvastatin 20 mg daily.
This case presents a commonly encountered clinical scenario with several treatment options. According to the 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Disease Risk, based on this patient's baseline, 10-year ASCVD risk of 16.0%, he is in a statin benefit group, and should be considered for statin therapy.1 For a patient aged 40-75 years without clinical ASCVD or diabetes with LDL-C 70-189 mg/dL and 10-year ASCVD risk ≥7.5%, the guideline recommends a discussion regarding high-intensity statin therapy (atorvastatin 40-80 mg daily, or rosuvastatin 20-40 mg daily) for primary ASCVD prevention. Based on large randomized controlled trials of statins, high-intensity statin therapy is associated with a mean reduction in LDL-C of ≥50% but there is considerable inter-individual variability in response to treatment.1,2 Monitoring of the lipid panel is important to assess both adherence and response to therapy.
Appropriate therapy was started in this case; however, the patient complaints of myalgias on atorvastatin 40mg daily. In addition, repeat lipid panel showed only a 35% LDL-C reduction on high-intensity statin, which is considered a less-than-expected LDL-C reduction. Treatment options may include: 1) stopping statin therapy until symptoms resolve, then restarting the same statin at original or lower dose to establish a causal relationship; or 2) discontinuing original statin if causal relationship exists and using a low dose of a different statin with gradual dose increase as tolerated.1 Statin intolerance should not be firmly diagnosed without rigorous and systematic evaluation of muscle symptoms and consideration of other causes of myalgias (hypothyroidism, vitamin D deficiency, physical activity, etc.). Generally, it is recommended that the patient has been tried on at least two to three different statins and doses, preferably with different metabolic pathways and lipophilicity/hydrophilicity before making the diagnosis of statin intolerance.2 Alternative statin dosing strategies may also be considered in patients with statin associated muscle symptoms, though randomized controlled trial evidence of ASCVD risk reduction is not available. With suboptimal LDL-C lowering in high-risk primary prevention patients on maximally tolerated statin therapy, the 2016 ACC Expert Consensus Decision Pathway of the Role of Non-Statin Therapies for LDL-C Lowering in the Management of ASCVD Risk recommends consideration of non-statin therapy with ezetimibe, followed by bile acid sequestrant as second-line treatment.2
This patient demonstrates the blurred boundaries between the definitions of "primary" and "secondary" prevention in the setting of extensive subclinical coronary atherosclerosis but without prior clinical ASCVD event. Given his symptoms of fatigue and exercise intolerance, high calcium score, and strong family history, one may also consider cardiac catheterization as the presence of obstructive atherosclerosis could alter the patient's management and treatment options. For example, the PCSK9 inhibitors are currently approved only for use in patients with "clinical ASCVD" or familial hypercholesterolemia on maximally tolerated statin therapy who need additional LDL-C lowering. In a patient with initial LDL-C 186 mg/dL and strong family history of premature coronary disease, one must also consider familial hypercholesterolemia given the phenotypic variability of this disorder. In patients with subclinical ASCVD with 10-year ASCVD risk greater than 7.5%, and suboptimal lipid lowering results, the PCSK9 inhibitors are not currently recommended in the ACC/AHA guidelines.2 However, in patients with familial hypercholesterolemia or clinical ASCVD, alirocumab and evolocumab may be considered if goals of therapy have not been achieved on maximally tolerated statin.2
In this patient, therapy was changed to rosuvastatin 20 mg daily to maintain treatment with a high-intensity statin, and he tolerated this without recurrence of myalgias. He was also started on non-statin therapy with ezetimibe 10mg daily. Repeat lipid panel demonstrated 50% reduction in LDL-C.
Stone NJ, Robinson JG, 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 2014;63:2889-934.
Lloyd-Jones DM, Morris PB, Ballantyne CM. 2016 ACC Expert Consensus Decision Pathway on the Role of Non-Statin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk: A Report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol 2016;68:92-125.