Dyslipidemia plays a dominant role in atherosclerotic plaque formation and as a modifiable risk factor for cardiovascular events.
Dyslipidemia plays a dominant role in atherosclerotic plaque formation and as a modifiable risk factor for cardiovascular events.1 Numerous studies have shown that lowering low-density lipoprotein cholesterol (LDL-C) and non–high-density lipoprotein cholesterol (non–HDL-C) can significantly reduce the number of cardiovascular disease events.2-5
The National Cholesterol Education Program Adult Treatment Panel III (ATP III) guidelines (http://circ.ahajournals.org/cgi/content/full/106/25/3143) and the 2004 ATP III update (http://circ.ahajournals.org/cgi/content/full/110/2/227) (see Table 1on page S2 in the accompanying article) define the optimal LDL-C goals for patients with or at risk for coronary heart disease (CHD) and the secondary non–HDL-C goals in patients with high triglycerides (≥ 200 mg/dL).6 The LDL-C and non–HDL-C targets for therapeutic lifestyle changes and drug therapy depend on a person’s near-term cardiovascular risk-the higher the risk, the lower the target levels. For persons without CHD, the ultimate goal of primary prevention is to reduce not only near-term but also lifetime risk of cardiovascular events by preventing or slowing the development of atherosclerosis.7
Statins are the first-line treatment to achieve LDL-C and non– HDL-C targets6 because they slow the progression of atherosclerosis and reduce the number of atherosclerotic outcomes.8,9 Some clinical studies since 2004 have compared the effects of intensive versus less intensive statin therapy or have evaluated the potential incremental benefits of combining statins with other lipid-modifying agents. In this review, I examine the results of these studies and their implications for the primary and secondary prevention of CHD.
INTENSIVE STATIN THERAPY FOR SECONDARY PREVENTION
In 2004, the ATP III guidelines were updated with evidence from several new controlled clinical studies of statins that evaluated cardiovascular outcomes. The LDL-C goal of < 100 mg/dL was maintained as a firm recommendation for patients at high risk for cardiovascular events; however, a goal of LDL-C < 70 mg/dL was recommended as an option for patients at very high risk.10 The rationale for this optional LDL-C goal of < 70 mg/dL was based on the results of the Heart Protection Society (HPS) and PROVE IT–TIMI 22 studies. A subgroup analysis of HPS showed that simvastatin compared with placebo significantly reduced the risk of a first major vascular event in participants with LDL-C < 116 mg/dL at baseline.11 Most importantly, PROVE IT–TIMI 22 (Table 1), which compared the effects of moderate and intensive statin therapy on a composite end point of cardiovascular events and all-cause death in patients with acute coronary syndrome (ACS), demonstrated that a median LDL-C level of 62 mg/dL in the intensive therapy group, compared with 95 mg/dL in the moderate therapy group, was associated with a statistically significant 16% relative risk reduction.12
Other recent comparative studies of intensive versus less intensive statin therapy in stable CHD and post-ACS secondary prevention have yielded mixed results (see Table 1). The A to Z study compared simvastatin 80 mg/d with simvastatin 20 mg/d in 4497 patients after ACS. After 8 months of treatment, median LDL-C was significantly lower (63 mg/dL) in those who had received intensive therapy than in those who had received lower statin dosages (77 mg/dL) (P < .001). Relative risk reduction after a follow-up of 6 to 24 months for the composite primary end point of cardiovascular death, myocardial infarction (MI), readmission to hospital for ACS, and stroke was 11% for intensive versus less intensive therapy, but the difference was not statistically significant. 13 However, a post hoc analysis revealed that although no difference was observed between intensive and less intensive therapy in the first 4 months, a significant (P = .02) 25% relative risk reduction was observed for the primary end point from month 4 to the end of the study.13
The TNT, IDEAL, and SEARCH studies (see Table 1) evaluated intensive versus moderate lipid-lowering strategies in patients with stable CHD. Participants in the TNT study who had a mean LDL-C level of 98 mg/dL after 8 weeks of open-label run-in treatment with atorvastatin 10 mg/d (baseline) had no further LDL-C improvement after randomization to continued low-dose atorvastatin but achieved a mean LDL-C of 77 mg/dL after randomization to atorvastatin 80 mg/d. Over 5 years, 80 mg/d of atorvastatin versus 10 mg/d provided a significant relative risk reduction of 22% for a first major cardiovascular event.14 In the IDEAL study, intensive therapy with atorvastatin 80 mg/d was associated with a greater numerical reduction in the incidence of major coronary events compared with simvastatin 20 mg/d, but the results did not reach statistical significance.15 SEARCH, the largest trial to evaluate the clinical benefits of intensive statin therapy, compared the effects of simvastatin 80 mg/d and 20 mg/d on major vascular outcomes in 12,064 survivors of MI.16 After 7 years of follow- up, a trend toward lower major cardiovascular event rates was observed for the higher versus the lower dose (6% relative risk reduction) but was not statistically significant.16 A meta-analysis of SEARCH, A to Z, TNT, IDEAL, and PROVE IT–TIMI 22 showed that reduction of LDL-C by 38 mg/dL was associated with a significant relative risk reduction of 28% (95% confidence interval, 22% to 34%; P < .0001) for major vascular events.17
The results of these outcomes trials have been corroborated by those of trials using surrogate measures of atherosclerosis, such as intravascular ultrasound. The REVERSAL study demonstrated that atorvastatin 80 mg/d was significantly more effective than pravastatin 40 mg/d in slowing the progression of atherosclerosis. 9 Further analyses of the results revealed a highly significant correlation between percentage reduction in atheroma volume and percentage reduction in LDL-C.18 Subsequently, results from the ASTEROID study demonstrated that patients, who served as their own control and received rosuvastatin 40 mg/d for 2 years, had significant regression of atherosclerosis by 3 prespecified measures of atheroma burden. On average, patients in this study achieved an LDL-C of 60.8 mg/dL and had an increase in HDL-C of 14.7%.19
Implications for practice. The results of secondary prevention studies that evaluated different intensities of statin therapy on cardiovascular outcomes or atherosclerotic disease progression provide strong evidence that greater reductions of LDL-C are associated with better clinical benefits. In addition, targeting LDL-C at or near 70 mg/dL can provide significant additional clinical benefits to high-risk patients, thus supporting this goal as a reasonable therapeutic option not only for very high-risk patients but for all patients with CHD. Consistent with this view, the American Heart Association and American College of Cardiology recommendations for the secondary prevention of cardiovascular events have LDL-C of < 70 mg/dL as a reasonable target for patients with CHD and other atherosclerotic diseases.20
INTENSIVE STATIN THERAPY: PRIMARY PREVENTION
Primary prevention studies have demonstrated that statins reduce the risk of major coronary events in persons without established CHD.21 Among the primary prevention studies, the JUPITER study is notable. It enrolled men older than 50 years and women older than 60 years with average LDL-C levels (median, 108 mg/dL) but elevated levels of the inflammation biomarker high-sensitivity C-reactive protein (hsCRP) (median, 4.3 mg/L).22 The participants were treated with rosuvastatin 20 mg/d or placebo.23
After 1 year of treatment, median LDL-C in the rosuvastatin group was 55 mg/dL, whereas LDL-C levels in the placebo group remained unchanged (median, 110 mg/dL). During the same period, median hsCRP levels decreased to 2.2 mg/L and 3.5 mg/L in rosuvastatin- and placebo- treated participants, respectively.23 After a median follow-up of only 1.9 years, the trial was stopped early because rosuvastatin significantly reduced the risk of the composite primary end point (MI, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes) by 44% compared with placebo (see Table 1).23 In addition, significant risk reduction was observed in the occurrence of the individual end points of MI (54%), stroke (48%), and arterial revascularization or unstable angina (47%).23 A prospective subgroup analysis of JUPITER demonstrated that participants who achieved on-treatment LDL-C levels of < 70 mg/dL and hsCRP levels of < 2 mg/L received the greatest clinical benefits (ie, a 65% relative risk reduction) versus placebo for the primary end point.24 The relative risk reduction, absolute risk reduction, and number needed to treat to prevent cardiovascular outcomes for the JUPITER population were comparable to those for other primary prevention studies.25
The METEOR study evaluated the effect of intensive statin therapy on progression of atherosclerosis in middle-aged asymptomatic persons with subclinical atherosclerosis, as measured by carotid intima-media thickness (CIMT).26 Participants had a 10-year Framingham risk score (FRS) of 10% or lower, a moderate degree of CIMT thickness, and a mean LDL-C level of 154 mg/dL. Rosuvastatin 40 mg/d lowered mean LDL-C levels to 78 mg/dL. Over a period of 2 years, rosuvastatin compared with placebo significantly slowed the progression of atherosclerosis, based on the assessment of maximum CIMT.26
Implications for practice. High hsCRP levels add important prognostic information for patients at all levels of LDL-C and at all levels of FRS.27 The results of the JUPITER study suggest that statin therapy can produce significant primary prevention benefits to older persons with high hsCRP levels who are at low risk for cardiovascular events based on FRS. Traditionally, such persons have not been considered for statin therapy. The results of the METEOR study further suggest that statins may provide benefits for asymptomatic patients with measurable subclinical atherosclerosis by slowing the progression of arterial wall thickening.
STATIN COMBINATION THERAPY
For patients with familial hypercholesterolemia (an uncommon autosomal dominant genetic disease) or with mixed dyslipidemia, the ATP III guidelines recommend a combination of a statin plus another lipid-modifying drug to achieve LDL-C and non–HDLC goals.6 However, at the time the guidelines were published, evidence from cardiovascular disease outcomes studies regarding the efficacy of combination therapies (eg, with ezetimibe, niacin, or fibrates) compared with statin monotherapy was not available.
The ACCORD Study Group compared the effects of simvastatin plus fenofibrate and simvastatin alone on clinical outcomes in patients with type 2 diabetes.28 Efficacy results showed that adding fenofibrate to simvastatin reduced triglyceride levels and raised HDL-C levels but had marginal effects on LDL-C levels. Most importantly, the addition of fenofibrate fell short of providing significant risk reduction benefits for the primary end point of death from cardiovascular causes, nonfatal MI, or nonfatal stroke (Table 2) or for any secondary end point. In a prespecified subgroup analysis, however, there was a trend toward clinical benefit of combination therapy versus monotherapy (31% relative risk reduction) in patients with high triglyceride (≥ 204 mg/dL) and low HDL-C (≤ 34 mg/dL) levels at baseline.28 Overall, the ACCORD Lipid study does not support the routine addition of fenofibrate to a statin to reduce cardiovascular risk in type 2 diabetes patients who do not have a clinically significant degree of mixed dyslipidemia at baseline.
Niacin is the most effective agent currently available for raising HDL-C levels.29 Several recent studies have evaluated the incremental effect of niacin plus a statin on surrogate cardiovascular outcomes.29 The ARBITER 2 study demonstrated that extended-release niacin, when added to existing statin therapy, raised HDL-C levels, reduced triglycerides, and slowed the progression of carotid atherosclerosis over 12 months in CHD patients with low baseline levels of HDL-C.30 Moreover, a subgroup from ARBITER 2 demonstrated additional increases in HDL-C and significant atherosclerosis regression over 24 months (ARBITER 3).31 The ARBITER 6-HALTS study found that extended-release niacin in high-risk patients treated with statins led to significant regression of CIMT compared with the addition of ezetimibe, a selective inhibitor of intestinal cholesterol absorption.32 Ongoing studies are evaluating the clinical outcomes of statin plus niacin combination therapy in patients with established cardiovascular disease (AIM-HIGH33 and HPS2-THRIVE34).
Addition of omega-3 fatty acids of marine origin to simvastatin has been shown to reduce triglyceride levels and raise HDL-C levels.35 The clinical benefits for Japanese patients of adding an omega-3 fatty acid to statin therapy were demonstrated in JELIS.36 The combination of eicosapentaenoic acid (EPA) 1.8 g and a statin was significantly more effective than a statin alone in reducing the incidence of major coronary events, especially nonfatal coronary events. Notably, addition of EPA to statin therapy reduced triglycerides but did not affect LDL-C levels.36 Other known biological effects of EPA, such as attenuation of thrombosis or inflammation, in addition to reduction of triglycerides could have contributed to the observed clinical benefits.37,38
Ezetimibe has become an important adjunctive therapy to statins for the reduction of elevated LDLC. 39,40 However, the results of a recent study that examined the effects of simvastatin/ezetimibe combination therapy on a surrogate measure of atherosclerosis were disappointing. The ENHANCE study found that combination therapy with ezetimibe and simvastatin compared with simvastatin alone decreased levels of LDL-C and C-reactive protein but had no additional beneficial effect on the CIMT measurement in patients with familial hypercholesterolemia.41 The outcomes benefit of ezetimibe/simvastatin in combination compared with simvastatin monotherapy is being evaluated in patients with stabilized ACS (IMPROVE-IT42) and in patients with chronic kidney disease (SHARP43).
Implications for practice. Statins are the cornerstone of treatment for dyslipidemia. Ezetimibe, fibrates, niacin, or omega-3 fatty acids are addon options for patients who fail to reach LDL-C and/or non–HDL-C targets with statin therapy alone. However, although these drugs improve lipid/lipoprotein measures, clinical evidence that they provide additional benefits to specific patient groups is insufficient. We await the outcome of ongoing comparative trials for clarification.
PATIENT ADHERENCE TO STATIN THERAPY
The benefits of statin treatment in high-risk persons with or without CHD demonstrated in clinical trials cannot be realized in clinical practice if patients do not take statins as prescribed. Adherence to lipid-lowering therapy in nonclinical trial settings is notoriously low: 50% after 6 months of treatment and 30% to 40% after 12 months of treatment.7 A recent, large, retrospective analysis of patients with and without CHD enrolled in a health maintenance organization showed that those who took statins more than 90% of the time had a 45% or greater reduction in the risk of death compared with those with less than 10% adherence. These results highlight the importance of initiating statins for appropriate at-risk patients and encouraging patients to comply with long-term treament.44
Adherence to prescribed medications may be promoted through proactive physician–patient communication. Because of the asymptomatic nature of dyslipidemia and, for many patients, atherosclerosis, most patients require frequent reminders of the long-term benefits of lipid-lowering treatment. Improving adherence starts with making sure that patients understand the causal relationship between cholesterol and CHD. Rapid achievement of lipid goals reduces the need for frequent return visits and laboratory tests, which may enhance patient adherence to treatment. The ATP III guidelines7 include a list of practical interventions for patients, physicians, medical offices, and health delivery systems to improve patient adherence to medication (available online at http://www.nhlbi.nih.gov/guidelines/cholesterol).
Implications for practice. Realization of the clinical benefits of statin therapy cannot be accomplished without engaged patients and a “champion” physician. A few extra moments of education about the prevention of atherosclerosis and its detrimental outcomes can greatly improve patient acceptance of and adherence to a long-term treatment such as statins.
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