Lipid Management in the Cardiac Care Unit
Merle Myerson
Prevention can take place at many levels. Primary prevention targets people who may have asymptomatic or preclinical coronary artery disease (CAD) or have risk factors for developing CAD. Secondary prevention targets people who have clinically manifest CAD. This chapter focuses on secondary prevention, in particular lipid management after acute coronary syndrome (ACS).
The American Heart Association and American College of Cardiology issued an update to their guidelines for secondary prevention in 2006. The statement emphasizes the importance of aggressive control of dyslipidemia.1 The principal author, Sidney Smith, comments that patients do not receive treatment for risk factors after ACS for many reasons. Hospital stays after heart procedures are short, which limits the time a patient can be educated.2 However, hospitalization after ACS represents an ideal time to work with patients to diagnose and treat dyslipidemia.
DEFINITION OF DYSLIPIDEMIA
Lipids are a group of naturally occurring molecules to which cholesterol and triglycerides belong. Risk for CAD has been focused primarily on low-density lipoprotein cholesterol (LDL-C) as well as high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG). LDL-C makes up approximately 65% of total serum cholesterol and each particle contains one apolipoprotein B-100. HDL-C makes up approximately 25% of total serum cholesterol and contains apolipoprotein A. The apolipoproteins are structural proteins that transport lipids and carry out other functions. TGs contain glycerol and three fatty acids.
Other lipid particles involved in atherosclerosis include apolipoprotein B (apoB), VLDL cholesterol, lipoprotein (a), and lipoprotein phospholipase A2. Subclasses of LDL (small, dense, large, or buoyant) and LDL particle number can also be measured. Of note, apoB levels reflect the number of atherogenic particles. One apoB particle is present on each LDL particle and is also present in other lipid particles.
Lipoprotein metabolism is complex and interrelated; a complete description is outside the scope of this chapter but more in-depth information can be found in several texts.3,4 and 5
In the mid-1960s, the Frederickson classification system for dyslipidemia was developed based on lipoprotein classes. Types I through V were described. This system was not particularly relevant to the clinician. There are also other classifications that include familial hypercholesterolemia (FH), familial combined hypercholesterolemia, hypertriglyceridemia, and low HDL-C.” FH is common; it is an autosomal codominant monogenic disorder primarily resulting from mutations in the LDL-receptor gene. Most people with FH are heterozygotes; homozygotes are rare at about one in one million persons and result in markedly elevated LDL starting at a young age.
The National Cholesterol Education Program Adult Treatment Program (NCEP ATP III) guidelines focus on LDL, HDL, and TG as targets for treatments. The guidelines also recommend calculating non-HDL cholesterol that closely approximates apoB levels, therefore the atherosclerotic burden. Non-HDL cholesterol is calculated as total cholesterol—HDL, that is, the difference of HDL from total cholesterol.
LDL has remained the primary target for those with either CAD or risk factors, and the NCEP guidelines stratify goals based on risk. All patients with CAD should have LDL <100 mg/dL with an optional goal of <70 mg/dL. HDL goals are ≥40 mg/dL and TGs are <150 mg/dL. Non-HDL cholesterol goal is 30 mg/dL greater than LDL goal. Of note, The revised guidelines (ATP IV) are scheduled to be published in 2012 and may have more aggressive goals.6
TREATMENT OF DYSLIPIDEMIA IN THE SETTING OF ACUTE CORONARY SYNDROME
During hospitalization for ACS, it is important to address risk factors prior to leaving the hospital to help in lowering the risk of having another event. Treatment of lipids is especially important as research suggests that statins have a role in the acute setting.
MEASUREMENT OF LIPIDS IN THE ACUTE SETTING
Lipid values are felt to be relatively stable in the outpatient population. TGs are influenced by the fasting or nonfasting state and therefore lipid profiles are generally obtained in the fasting state. However, LDL, HDL, and TG are considered acute phase reactants, and their levels will be altered in ACS: HDL and LDL decrease whereas TG increases.
As indicated in figure 34.1, it is important to determine the onset of ACS and obtain a fasting lipid panel within 24 hours, if possible. Research has shown that lipids levels begin to alter within 24 hours and continue to change for approximately 7 days. Levels return to baseline at about 4 weeks. Greater changes are seen with larger and more severe infarcts with peak LDL decreases up to 30% of baseline.7,8 and 9 Pitt et al.10 examined
507 ACS patients and found that LDL levels decreased in the first 24 hours after admission followed by an increase over the next 2 days, a change that did not appear to be clinically meaningful. Similar changes were seen with total cholesterol and HDL, although fasting TG levels did not change.
507 ACS patients and found that LDL levels decreased in the first 24 hours after admission followed by an increase over the next 2 days, a change that did not appear to be clinically meaningful. Similar changes were seen with total cholesterol and HDL, although fasting TG levels did not change.
Levels may also be influenced by prior treatment with lipid medications although it is unclear how much preexisting treatment may influence degree of change in the setting of ACS.
Ideally a lipid panel should be obtained on presentation to the hospital. If the time of onset of ACS is unclear, a lipid panel will be still helpful to estimate presence and extent of dyslipidemia. Secondary causes of dyslipidemia should also be considered including hypothyroidism, nephritic syndrome, obstructive liver disease, chronic renal failure, and use of LDL-altering drugs (progestins, anabolic steroids, estrogen, corticosteroids, and protease inhibitors for the treatment of HIV disease).
Total cholesterol, HDL cholesterol, and TG should be measured. For patients with TG <400 mg/dL LDL is generally calculated using the Friedewald formula. For patients with TG >400 mg/dL most labs will automatically perform a direct measurement of LDL cholesterol. It is helpful to have liver function tests (AST, ALT) and creatinine kinase (CK) to evaluate patients who may not be able to tolerate some lipid medications. Also recommended is thyroid-stimulating hormone (TSH) to screen for thyroid disease.
BENEFIT OF LIPID TREATMENT IN ACUTE CORONARY SYNDROME
Research supports the use of lipid-lowering therapy, in particular statin use, in the setting of ACS. Less known are the benefits of other drugs such as niacin, bile acid sequestrants, intestinal absorption inhibitors, and Ω-3 fatty acids. As indicated in figure 34.1, research to date suggest giving atorvastatin 80 mg for patients with ACS if there are no contraindications.
The MIRACL Study was a randomized, double-blind trial in the late 1990s enrolling 3,086 patients with unstable angina or non-Q wave myocardial infarction (NQWMI). Patients received 80 mg a day of atorvastatin or placebo between 24 and 96 hours after hospital admission and followed for 16 weeks. There were no significant differences in death, nonfatal MI, or coronary revascularization between the two groups but the atorvastatin group had less symptomatic ischemia episodes requiring emergency hospitalization.11
The PROVE IT-TIMI 22 trial enrolled 4,162 patients with ACS occurring within the previous 10 days and were randomly assigned 80 mg atorvastatin daily (labeled “intensive lipid lowering”) or pravastatin 40 mg daily (“moderate lipid lowering”). Patients were followed up for 2 years. The endpoints of death, reinfarction, stroke, recurrent unstable angina, and coronary revascularization were reduced from 26.3% in the pravastatin group to 22.4% in the atorvastatin group, and this difference was significant at P = .005.12
In the A to Z trial, approximately 4,500 patients with ACS were enrolled and randomized to either simvastatin 40 mg daily for 1 month followed by 80 mg a day or placebo for 4 months followed by simvastatin 20 mg a day for 4 months. Follow up was for 6 months at least and up to 24 months. Cardiovascular death occurred in 4.1% in the first group and 5.4% in the second group (P = .05), but there were no other differences in the other primary endpoints.13 Factors felt to have influenced the lack of positive findings in the A to Z trial include intensity and timing of therapy.
A more recent study, the Japan assessment of pitavastatin and atorvastatin in ACS (JAPAN-ACS) study, was a randomized, open-label parallel group study in Japan of 252 ACS patients undergoing intravascular ultrasound (IVUS)-guided percutaneous coronary intervention. Patients received either 4 mg of pitavastatin or 20 mg of atorvastatin daily. Subjects underwent repeat IVUS at 8 and 12 months to assess percentage change in nonculprit coronary plaque volume (PV). Both drug regimens achieved significant reduction in PV with neither agent demonstrating superiority.14
STATIN USE IN ACS PATIENTS UNDERGOING PERCUTANEOUS CORONARY INTERVENTION
Several studies have investigated whether statin use benefits ACS patients undergoing percutaneous coronary intervention (PCI). In the ARMYDA-ACS trial, 171 patients with NSTEMI going for PCI were randomized to pretreatment with atorvastatin 80 mg, 12 hours before with further 40 mg preprocedure dose or placebo. After PCI all patients were given atorvastatin 40 mg daily. Periprocedure infarct, elevation of creatine kinase-MB and troponin-I was less in the pretreated group demonstrating a short-term benefit of statins in ACS patients undergoing PCI.15
A substudy PROVE IT-TIMI 22 investigated patients who had ACS and underwent PCI who received either atorvastatin 80 mg or pravastatin 40 mg daily. The atorvastatin group had less all-cause mortality, myocardial infarction, unstable angina leading to hospitalization, and revascularization after 30 days.16
MECHANISMS BY WHICH STATINS CONFER BENEFIT IN ACS
All studies showed greater LDL lowering with statin, or in the case of PROVE IT TIMI 22, greater lowering with atorvastatin 80 mg compared with pravastatin 40 mg daily. However, benefits were seen in the short term perhaps before the lower LDL could have conferred benefits. In addition, statins have been shown to have non-LDL lowering or pleiotropic effects. Statins have also been shown to reduce inflammation (a component of ACS), be antithrombic, and improve endothelial function all of which may be beneficial for ACS patients.17
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