Circulation Editors’ Picks

Abstract

HomeCirculationVol. 128, No. 10Circulation Editors’ Picks Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBCirculation Editors’ PicksMost Read Articles on the Topic of Secondary Prevention The Editors The Editors Search for more papers by this author Originally published3 Sep 2013https://doi.org/10.1161/CIRCULATIONAHA.113.005495Circulation. 2013;128:e141–e155Concomitant Use of Antiplatelet Therapy with Dabigatran or Warfarin in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY®) TrialSummary—Oral anticoagulants are indicated for the prevention of stroke and systemic embolism in patients with atrial fibrillation at risk of stroke. However, the risks and benefits of oral anticoagulants are affected by the addition of antiplatelet drugs, which are commonly needed by these patients for concurrent conditions like coronary artery disease. In this study, we tried to quantify the impact of concomitant antiplatelets on the relative efficacy and safety of dabigatran etexilate (DE) and warfarin in patients with atrial fibrillation. Our results showed that, whether or not patients were on antiplatelet agents, DE given at 150 mg BID reduced stroke and systemic embolism to a greater extent than warfarin, with no increase in the rate of major bleeding. In contrast, DE given at 110 mg BID reduced stroke and systemic embolism to the same extent as warfarin, but with substantially lower rates of major bleeds, irrespective of whether patients were on other antiplatelet drugs or not. Addition of antiplatelet agents was associated with higher risks of bleeding with all the oral anticoagulants in our study. The relative increase in the risk of major bleed was 1.6-fold on a single antiplatelet and 2.3-fold on double antiplatelets. However, the absolute risk of bleeding was lowest on DE given at 110 mg BID. Therefore, in patients needing concomitant antiplatelets, DE has the advantage of 2 dose options: one that maximizes the effectiveness (DE given at 150 mg BID) and another that maximizes safety (DE given at 110 mg BID). Clinicians and patients can select the most appropriate dose to use, depending on the inherent risks for stroke and systemic embolism or hemorrhage of each patient.Conclusions—Concomitant antiplatelet drugs appeared to increase the risk for major bleeding in RE-LY without affecting the advantages of dabigatran over warfarin. Choosing between DE110 and DE150 requires a careful assessment of characteristics that influence the balance between benefit and harm.1An Early Appointment to Outpatient Cardiac Rehabilitation at Hospital Discharge Improves Attendance at Orientation: A Randomized, Single-Blind, Controlled TrialSummary—Outpatient cardiac rehabilitation (CR) is a highly effective but significantly underutilized intervention for patients after an acute myocardial infarction, percutaneous coronary intervention, or cardiac surgery. The mortality reduction from CR is similar to that seen with statin medications (range 20% to 35%), yet only ≈30% of eligible patients participate in CR. National organizations, including the American Heart Association, have called for improvement of this important quality gap. One contributing modifiable factor may be the timing of the first appointment for CR. Recent retrospective studies have suggested that for each day of delay between hospital discharge and CR orientation, there is a 1% loss in CR participation. We prospectively randomized 148 patients to receive either an early or standard appointment to CR. Attendance occurred at a median of 8 versus 42 days per group, respectively. We found a significant 18% absolute and 56% relative improvement in attendance at orientation in the early group. Although the effects of an early appointment were limited to attendance at orientation, this technique was simple, safe, and was easily incorporated into the referral routine. Consequently, when coupled with other known effective techniques (automatic-referral and liaison-facilitated referral), an early appointment could potentially increase patient participation in CR and reduce the size of this important quality gap in the secondary prevention of heart disease.Conclusions—Early appointments for CR significantly improve attendance at orientation. This simple technique could potentially increase initial CR participation nationwide.2Effects of Interleukin-1β Inhibition With Canakinumab on Hemoglobin A1c, Lipids, C-Reactive Protein, Interleukin-6, and Fibrinogen: A Phase IIb Randomized, Placebo-Controlled TrialSummary—Atherosclerosis in an inflammatory condition, and biomarkers of inflammation including CRP, IL-6, and fibrinogen associate with increased vascular risk. However, whether inhibiting inflammation will reduce vascular events is uncertain. One promising anti-inflammatory approach with potential relevance for cardiovascular disease is inhibition of the proinflammatory cytokine IL-1, particularly the IL-1β isoform that is secreted and acts locally but that also induces systemic effects. In a phase IIb randomized trial conducted among high-risk diabetic patients comparing placebo with canakinumab, a monoclonal antibody targeting IL-1β, we observed statistically significant dose-dependent reductions in all 3 of these inflammatory biomarkers without major effect on LDL-C or HDL-C. There were no differences in clinical adverse events between active and placebo patients, although a small increase in triglycerides was observed at higher canakinumab doses. These phase II trial data support the use of canakinumab as a potential therapeutic method to test directly the inflammatory hypothesis of atherosclerosis. Indeed, in part on the basis of these data, a large-scale multinational hard outcomes trial, CANTOS, is being conducted that will address directly whether inhibition of IL-1β with canakinumab can reduce recurrent vascular event rates in a high-risk secondary prevention population.Conclusions—Canakinumab, a human monoclonal antibody that neutralizes interleukin-1β, significantly reduces inflammation without major effect on low-density lipoprotein cholesterol or high-density lipoprotein cholesterol. These phase II trial data support the use of canakinumab as a potential therapeutic method to test directly the inflammatory hypothesis of atherosclerosis.3Apolipoprotein B Synthesis Inhibition With Mipomersen in Heterozygous Familial Hypercholesterolemia: Results of a Randomized, Double-Blind, Placebo-Controlled Trial to Assess Efficacy and Safety as Add-On Therapy in Patients With Coronary Artery DiseaseSummary—Heterozygous familial hypercholesterolemia is a common genetic disorder that leads to premature coronary artery disease. Despite aggressive lipid-lowering therapy, many patients with heterozygous familial hypercholesterolemia fail to achieve optimal low-density lipoprotein cholesterol (LDL-C) goals. We evaluated mipomersen, an apolipoprotein B synthesis inhibitor, to further lower LDL-C in patients with heterozygous familial hypercholesterolemia with coronary artery disease who were already on maximally tolerated lipid-lowering therapy and had LDL-C >2.6 mmol/L (100 mg/dL). The phase 2, double-blind, placebo-controlled trial randomized 124 patients (41 placebo, 83 mipomersen) to weekly subcutaneous mipomersen 200 mg or placebo (2:1) for 26 weeks. The primary end point was percent change in LDL-C from baseline at week 28. Safety assessments included adverse events, laboratory tests, and MRI assessment of hepatic fat. Mean LDL-C decreased 28.0% with mipomersen compared with a 5.2% increase with placebo (P<0.001), and 45.1% compared with 4.9% achieved LDL-C <2.6 mmol/L (100 mg/dL), respectively. Mipomersen significantly (P<0.001) reduced apolipoprotein B (−26.3%) and lipoprotein(a) (−21.1%) compared with placebo. More frequent and severe injection site reactions occurred with mipomersen, and 5 mipomersen-treated patients (6%) had 2 consecutive alanine aminotransferase levels ≥3 times the upper limit of normal at least 7 days apart; none were associated with significant bilirubin increases. Hepatic fat content increased a median of 4.9% with mipomersen versus 0.4% with placebo (P<0.001). The clinical implications of such increases in hepatic fat and transaminase elevations are unclear and must be elucidated in longer-term studies. We conclude that mipomersen is effective to further reduce apolipoprotein B–containing lipoproteins, including LDL and lipoprotein(a), in patients with heterozygous familial hypercholesterolemia with coronary artery disease on statins and other lipid-lowering therapy.Conclusions—Mipomersen is an effective therapy to further reduce apolipoprotein B–containing lipoproteins, including LDL and lipoprotein(a), in HeFH patients with coronary artery disease on statins and other lipid-lowering therapy. The significance of hepatic fat and transaminase increases remains uncertain at this time.4Variation in Warfarin Dose Adjustment Practice Is Responsible for Differences in the Quality of Anticoagulation Control Between Centers and Countries: An Analysis of Patients Receiving Warfarin in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) TrialSummary—The outcome of atrial fibrillation patients on warfarin partially depends on maintaining adequate time in therapeutic International Normalized Ratio (INR) range (TTR). Large differences in TTR have been reported between centers and countries, but the reasons are unclear. In the Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial, a warfarin dosing algorithm provided to participating centers recommended no change for in-range and 10% to 15% weekly dose changes for out-of-range INR values. We determined whether algorithm-consistent warfarin dosing could predict patient TTR and the composite outcome of stroke, systemic embolism, or major hemorrhage. Among 6022 nonvalvular atrial fibrillation patients from 44 countries, we found a strong association between the proportion of algorithm-consistent warfarin doses and mean country TTR (R2=0.65). The degree of algorithm-consistent warfarin dosing accounted for a majority of the TTR variation between centers and countries. Each 10% increase in center algorithm-consistent dosing independently predicted a 6.12% increase in TTR (95% confidence interval, 5.65–6.59), and an 8% decrease in rate of the composite clinical outcome (hazard ratio, 0.92; 95% confidence interval, 0.85–1.00). In summary, warfarin dosing practice that does not change the dose when the INR is in range, and that makes relatively small (10% to 15%) weekly dose adjustments when the INR is out of range, is associated with improved TTR and clinical outcomes. Systems that implement algorithm-based dosing for patients with atrial fibrillation on warfarin could potentially improve outcomes on a global scale, especially in centers and countries with suboptimal INR control.Conclusions—Adherence, intentional or not, to a simple warfarin dosing algorithm predicts improved TTR and accounts for considerable TTR variation between centers and countries. Systems facilitating algorithm-based warfarin dosing could optimize anticoagulation quality and improve clinical outcomes in atrial fibrillation on a global scale.5Predictors of Early and Late Enrollment in Cardiac Rehabilitation, Among Those Referred, After Acute Myocardial InfarctionSummary—Cardiac rehabilitation (CR) is a key component of the comprehensive care of acute myocardial infarction (AMI) patients and is a Class I recommendation after AMI. While improving the use of CR has been a longstanding goal for quality improvement, there remains a gap between referral to CR and subsequent participation. In our study, despite a high CR referral rate of 66% post-AMI, only 29% referred patients participated in CR at 1-month and less than half participated at 6-months after AMI, making it an important quality improvement target. Several patient-oriented and medical factors affect early and late CR enrollment even after receiving CR referral after AMI. Women, the uninsured, and patients with hypertension, peripheral arterial disease, lower physical function, and prior percutaneous coronary intervention are less likely to participate at 1-month while non-Caucasians, older individuals, smokers and individuals with economic burden were less likely to participate at 6-months after AMI. These individuals represent populations at significantly increased cardiovascular risk who may benefit from the more intense secondary prevention services provided in CR. Since CR is associated with beneficial changes in cardiovascular risk factors and better outcomes, more aggressive efforts to increase CR participation after AMI are needed. There are still substantial gender and socio-economic disparities in CR use that will require additional interventions to overcome. While creating a performance measurement for referral is an important first step, creating a second measure to examine actual participation might be a successful adjunct to insure participation if proper denominator specifications can be created.Conclusions—Among patients referred for CR post-AMI, participation remains low both at 1 and 6 months after AMI. Because CR is associated with beneficial changes in cardiovascular risk factors and better outcomes after AMI, more aggressive efforts are needed to increase CR participation after referral.6Cardiovascular Risk of High- Versus Moderate-Intensity Aerobic Exercise in Coronary Heart Disease PatientsSummary—High level of physical fitness and regular exercise are closely related to cardiovascular health and reduced risk of cardiovascular disease and mortality. Aerobic exercise is therefore strongly recommended for patients with coronary heart disease. Exercise performed at higher relative intensities has been found to elicit greater increase in aerobic capacity and greater cardioprotective effects than exercise at moderate intensities. Despite that higher levels of physical activity are found to reduce cardiovascular events, it is advocated that vigorous activity could also acutely and transiently increase the risk of sudden cardiac events in susceptible persons. We therefore studied the risk of cardiovascular events during organized high-intensity interval exercise training and moderate-intensity training among 4846 coronary heart disease patients in 4 Norwegian cardiac rehabilitation centers. The event rate after patients were exposed to both types of exercise training was low. In a total of 175 820 exercise training hours where all patient performed both types of training, we found 1 fatal cardiac arrest during moderate-intensity exercise (129 456 exercise hours) and 2 nonfatal cardiac arrests during high-intensity interval exercise (46 364 exercise hours). There were no myocardial infarctions in the data material. Because the number of high-intensity training hours was 36% of the number of moderate-intensity hours, the rates of complications to the number of patient-exercise hours were 1 per 129 456 of moderate-intensity exercise and 1 per 23 182 of high-intensity exercise. We believe that our study provides needed knowledge about the risk of high-intensity exercise training for patients undergoing secondary cardiac rehabilitation.Conclusions—The results of the current study indicate that the risk of a cardiovascular event is low after both high-intensity exercise and moderate-intensity exercise in a cardiovascular rehabilitation setting. Considering the significant cardiovascular adaptations associated with high-intensity exercise, such exercise should be considered among patients with coronary heart disease.7Missed Opportunities: Despite Improvement in Use of Cardioprotective Medications Among Patients With Lower-Extremity Peripheral Artery Disease, Underuse RemainsSummary—One of the main goals for treatment of peripheral artery disease (PAD) is risk factor modification and secondary prevention of vascular events by initiating cardioprotective pharmacotherapies. Studies investigating temporal trends and longitudinal use of cardioprotective agents after incident diagnosis of PAD have been limited. With the use of Danish nationwide administrative registries, which capture medication adherence, we demonstrate a significant temporal improvement from 2000 to 2007 in the use of any antiplatelet and statin therapy after incident diagnosis of PAD. However, the use of these medications is modest, such that by 18 months after incident diagnosis, nearly half of patients with PAD alone are not taking any antiplatelet or statin therapy. After adjustment, patients with incident PAD and a history of coronary artery disease are more likely to take cardioprotective medications than patients with incident coronary artery disease alone (no history of PAD). Meanwhile, patients with PAD alone have nearly half the adjusted odds of taking any antiplatelet in comparison with patients with coronary artery disease alone. Although use of cardioprotective medications improved after publication of the American College of Cardiology/American Heart Association PAD guidelines in 2005, the adjusted odds of any antiplatelet use among patients with PAD alone, compared with patients with coronary artery disease alone, was nearly 35% less, and statin use was 20% less in a more contemporary period (2005–2007). The present analysis underscores the need for systemwide improvements to improve adherence to secondary prevention in this population.Conclusions—Despite improvement in the use of cardioprotective medications over time, patients with PAD alone remain less likely than those with CAD alone to use these agents.8Bleeding After Initiation of Multiple Antithrombotic Drugs, Including Triple Therapy, in Atrial Fibrillation Patients Following Myocardial Infarction and Coronary Intervention: A Nationwide Cohort StudySummary—Uncertainty remains regarding optimal antithrombotic treatment of patients with atrial fibrillation presenting with myocardial infarction or undergoing coronary intervention. Present expert statements (Level C evidence) recommend triple therapy with aspirin, clopidogrel, and vitamin K antagonist, with treatment limited to as short a time as possible because of a perceived greater risk of bleeding with prolonged treatment. In the current study, we examined the risk of bleeding associated with different antithrombotic treatment regimens in a nationwide real-life cohort of patients with atrial fibrillation and myocardial infarction and/or coronary intervention. We demonstrated an immediately high risk of bleeding with triple therapy that decreases over time. Nevertheless, the risk was continually elevated in comparison with less intense antithrombotic regimens, which suggests that triple therapy has no safe therapeutic window. No benefit was present for a combined thromboembolic end point of cardiovascular death, myocardial infarction, and ischemic stroke for triple therapy relative to vitamin K antagonist plus a single antiplatelet agent. Until data from randomized trials are available, our results suggest that triple therapy should only be prescribed after careful evaluation of bleeding risk.Conclusions—High risk of bleeding is immediately evident with triple therapy (TT) after myocardial infarction/percutaneous coronary intervention in patients with atrial fibrillation. A continually elevated risk associated with TT indicates no safe therapeutic window, and TT should only be prescribed after thorough bleeding risk assessment of patients.9Cardiac Rehabilitation Attendance and Outcomes in Coronary Artery Disease PatientsSummary—Cardiac rehabilitation (CR) is a well-endorsed but underused modality for treating patients with known coronary artery disease. The objectives of this study were to examine the use of CR by assessing CR attendance after referral and to assess the relationship between completion of CR and outcomes of mortality and resource use in a large cohort of CR patients referred for CR. A prospective analysis of a well-described cohort of subjects referred for CR was undertaken. Of 5886 subjects referred to CR, only 2900 (49.3%) completed the program, with men more likely to complete CR than women (52.1% versus 38.4%; P<0.001). Median follow-up was 5.37 years (interquartile range, 3.24–8.87 years). CR completion was associated with reduced mortality (hazard ratio, 0.57; 95% confidence interval, 0.46–0.66), reduced hospitalization (hazard ratio, 0.75; 95% confidence interval, 0.69–0.81), and reduced cardiac hospitalization (hazard ratio, 0.61; 95% confidence interval, 0.51–0.74). Using propensity scores, we matched 2256 CR completers to noncompleters. In the propensity-matched cohort, CR remained associated with improved mortality (hazard ratio, 0.67; 95% confidence interval, 0.54–0.81). These findings confirm reduced mortality in association with CR as seen in other studies, but in a larger, better-described population, while also newly demonstrating a significant reduction in hospitalization. Given the increasing number of subjects surviving initial cardiac events, the importance of completing a CR program to reduce future risk of hospitalization and mortality needs to be recognized.Conclusions—Among those coronary artery disease patients referred, CR completion is associated with improved survival and decreased hospitalization. There is a need to explore reasons for nonattendance and to test interventions to improve attendance after referral.10Vitamin D May Not Improve Lipid Levels: A Serial Clinical Laboratory Data StudySummary—Vitamin D deficiency is common. Low levels of serum 25-hydroxyvitamin D [25(OH)D], the biomarker of vitamin D status, are associated with cardiovascular risk factors, including dyslipidemia. However, clinical trials have yet to show a role for vitamin D repletion in reducing cardiovascular disease or improving the lipid profile. Prospective trials of vitamin D supplementation are underway but will take years to complete and are extremely expensive. We analyzed the Quest Diagnostics clinical database as an expedient and cost-effective method of investigating the relationship between 25(OH)D levels and blood lipids. This study provided data from a clinically relevant, “real-world” setting to verify the cross-sectional associations between 25(OH)D deficiency and the lipid profile. In the same population, we explored whether changes in 25(OH)D from the deficient range (<20 ng/mL) to the optimal range (30–100 ng/mL) were associated with beneficial effects on blood lipids. Our cross-sectional analysis found that higher 25(OH)D levels strongly correlated with a healthier lipid profile: lower total and low-density lipoprotein cholesterol, higher high-density lipoprotein cholesterol, and lower triglycerides. In contrast, our longitudinal analysis found that raising 25(OH)D levels from <20 to ≥30 ng/mL did not have an effect on low-density lipoprotein cholesterol or triglycerides, whereas total and high-density lipoprotein cholesterol both increased <1 mg/dL. Thus, it is misleading to conflate the epidemiological association of low 25(OH)D levels and dyslipidemia with a presumed benefit of vitamin D supplementation. Until long-term studies are available, clinicians should be cautious and should not expect that vitamin D supplementation will treat hypercholesterolemia in patients who are vitamin D deficient.Conclusions—Although vitamin D deficiency is associated with an unfavorable lipid profile in cross-sectional analyses, correcting for a deficiency might not translate into clinically meaningful changes in lipid concentrations; however, data from intervention trials are required to confirm these findings.11Influenza Vaccination and Major Adverse Vascular Events in High-Risk PatientsSummary—It remains uncertain whether the influenza vaccine is associated with a reduced risk of vascular events, despite at least 10 observational studies and 3 small randomized controlled trials investigating this association. The existing observational studies were limited by small size, involved only a single influenza season, and/or were at risk of significant bias resulting from study design and the presence of confounding. The 3 randomized controlled trials were small with few event rates, precluding any definitive conclusions. We therefore performed an observational study using data from a large multinational trial of patients at high risk for vascular events involving 31 546 participants from 733 centers in 40 countries. Although initial analyses suggest that influenza vaccination was associated with a reduced risk of major adverse vascular events during influenza seasons when the influenza vaccine matched the circulating virus, detailed sensitivity analyses revealed that evidence of risk of confounding bias remained. A randomized trial is needed to definitively address this question.Conclusions—Although initial analyses suggest that influenza vaccination was associated with reduced risk of major adverse vascular events during influenza seasons when the influenza vaccine matched the circulating virus, sensitivity analyses revealed that risk of bias remained. A randomized trial is needed to definitively address this question.12Determinants of Residual Risk in Secondary Prevention Patients Treated With High- Versus Low-Dose Statin Therapy: The Treating to New Targets (TNT) StudySummary—Cardiovascular risk among statin-treated individuals remains high and has been called residual risk, but the mechanisms underlying this residual risk are uncertain. Hence, we aimed to identify determinants of this risk above and beyond lipid-related risk factors in a secondary prevention population that achieved low low-density lipoprotein cholesterol targets. The study population comprised 9251 coronary patients with low-density lipoprotein cholesterol <130 mg/dL randomized to double-blind atorvastatin 10 or 80 mg/d in the Treating to New Targets (TNT) study who had complete on-treatment 1-year lipid data. Median follow-up was 4.9 years. The primary end point was major cardiovascular events (n=729): coronary death, nonfatal myocardial infarction, resuscitation after cardiac arrest, or fatal or nonfatal stroke. Multivariable determinants of increased risk were older age, increased body mass index, male sex, hypertension, diabetes mellitus, baseline apolipoprotein B and blood urea nitrogen, current smoking, prior cardiovascular disease, and calcium channel blocker use. Determinants of decreased risk were high-dose statin, aspirin use, and baseline apolipoprotein A-I. These known baseline clinical and lipid-related variables performed moderately well in discriminating future cases from noncases. On-treatment 1-year levels of lipids and apolipoproteins were not selected into the multivariable model because they were not associated with risk after baseline apolipoproteins and clinical risk factors were taken into account. In sum, residual risk among statin-allocated coronary patients was related to baseline lipid-related and nonlipid risk factors. Thus, a multifaceted secondary prevention approach targeting modifiable risk factors should be underscored as the cornerstone of optimal residual risk assessment and prevention.Conclusions—Determinants of residual risk in statin-treated secondary prevention patients included lipid-related and nonlipid factors such as baseline apolipoproteins, increased body mass index, smoking, hypertension, and diabetes mellitus. A multifaceted prevention approach should be underscored to address this risk.13Short- Versus Long-Term Duration of Dual-Antiplatelet Therapy After Coronary Stenting: A Randomized Multicenter TrialSummary—This study focusing on 2013 patients undergoing coronary stent implantation who received bare-metal, zotarolimus-eluting, paclitaxel-eluting, or everolimus-eluting stent implantation and were subsequently allocated to up to 6 months versus 24 months of clopidogrel therapy in addition to aspirin failed to show the anticipated superiority of long-term duration of dual-antiplatelet therapy in terms of a lower composite ischemic end point of overall death, myocardial infarction, or cerebrovascular accidents. The cumulative risk of the primary outcome at 2 years was 10.1% with 24-month dual-antiplatelet therapy compared with 10.0% with 6-month dual-antiplatelet therapy (hazard ratio, 0.98; 95% confidence interval, 0.74–1.29; P=0.91). The individual risks of death, myocardial infarction, cerebrovascular accident, or stent thrombosis did not differ between the study groups; however, there was a consistently greater risk of hemorrhage in the 24-month clopidogrel group according to all prespecified bleeding definitions, including the recently proposed Bleeding Academic Research Consortium classification. Two Korean studies have also previously reported a lack of benefit of either 12 or 24 months of clopidogrel therapy over 6 or 12 months of therapy, respectively. Therefore, altogether, the available evidence does not support the concept that the longer the duration of clopidogrel therapy after drug-eluting stent implantation, the better the outcomes. On the contrary, this study identifies the potential for harm with respect to major bleeding associated with prolonged use of dual-antiplatelet therapy.Conclusions—A regimen of 24 months of clopidogrel therapy in patients who had received a balanced mixture of drug-eluting or bare-metal stents was not significantly more effective than a 6-month clopidogrel regimen in reducing the composite of death due to any cause, myocardial infarction, or cerebrovascular accident.14Global Variation in the Prevalence of Elevated Cholesterol in Outpatients With Established Vascular Disease or 3 Cardiovascu