Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Use of intensive lipid-lowering therapy in patients hospitalized with acute coronary syndrome: An analysis of 65,396 hospitalizations from 344 hospitals participating in Get With The Guidelines (GWTG) Usman Javed, MD, a Prakash C. Deedwania, MD, a Deepak L. Bhatt, MD, MPH, b Christopher P. Cannon, MD, b David Dai, PhD, c Adrian F. Hernandez, MD, MHS, c Eric D. Peterson, MD, MPH, c and Gregg C. Fonarow, MD d Fresno and Los Angeles, CA; Boston, MA; and Durham, NC Objectives The study aimed to analyze the use of intensive lipid-lowering therapy (LLT) at discharge in a broad population of patients hospitalized with acute coronary syndrome (ACS). Background Early and intensive statin therapy in ACS was shown to reduce cardiovascular morbidity and mortality. Utilization and predictors of LLT among hospitalized ACS patients are not known. Methods The GWTG database was analyzed for ACS-related hospitalizations from 2005 to 2009. The use of LLT (defined as dose of statin or combination therapy likely to produce N50% reductions in low-density lipoprotein [LDL]) and less intensive LLT at discharge was assessed. Baseline characteristics and temporal trends in LLT were compared in these 2 treatment groups. Results Of 65,396 patients receiving LLT, only 25,036 (38.3%) were treated with an LLT regimen. Mean total cholesterol, LDL, and triglycerides were significantly higher in the LLT group. Even among those with LDL N130 mg/dL, 50% or less received LLT. Predictors of LLT at discharge included LLT before admission, hyperlipidemia, prior coronary artery disease, increasing body mass index, and in-hospital percutaneous coronary intervention. Although there was some temporal improvement in the rate of LLT from 2005 to 2007, a decline in use of LLT was noted in 2008 and 2009. This was attributed to a sharp reduction in use of ezetimibe in combination with statin, without corresponding increases in intensive statin monotherapy. Conclusions In a large cohort of patients admitted with ACS, most of the eligible patients were not discharged on LLT. These data suggest the need for better implementation of guideline-recommended intensive statin therapy in patients with ACS. (Am Heart J 2010;160:1130-1136.e3.) Several large studies have consistently demonstrated that lipid-lowering therapy (LLT) with 3-hydroxy-3methylglutaryl coenzyme A reductase inhibitors (statins) reduce cardiovascular risk irrespective of underlying coronary artery disease (CAD).1 In patients with stable CAD and acute coronary syndrome (ACS), statin therapy has shown a reduction in mortality and recurrent cardiac From the aUniversity of California, San Francisco-Fresno Medical Education Program, Fresno, CA, bVA Boston Healthcare System and Brigham and Women's Hospital, Harvard Medical School, Boston, MA, cDuke University Medical Center, Durham, NC, and d University of California, Los Angeles School of Medicine, Los Angeles, CA. Guest Editor: Vera Bittner, MD, MSPH. Submitted May 6, 2010; accepted August 24, 2010. Reprint requests: Prakash C. Deedwania, MD, Cardiology Section, UCSF Program at Fresno, 2615 E. Clinton Avenue (111), Fresno, CA, 93703. E-mail: [email protected] 0002-8703/$ - see front matter Published by Mosby, Inc. doi:10.1016/j.ahj.2010.08.041 events.2-6 These data have established a very early clinical benefit that persisted on long-term follow-up. The PROVE IT-TIMI 225 and MIRACL6 trials have shown even better clinical outcomes with early and intensive statin therapy in ACS. It is also well established that the adherence to the use of statin therapy in the post-ACS patient is directly related to statin initiation during the index admission.7 In light of above the evidence, the recent National Cholesterol Education Program Adult Treatment Panel guideline update recommended an optional low-density lipoprotein (LDL) treatment goal of b70 mg/dL for patients with ACS.8,9 Moreover, the current guidelines of the American College of Cardiology/American Heart Association (ACC/AHA) recommend measurement of lipid levels on admission and instituting LLT before hospital discharge in patients with ACS.10,11 The objective of our study was to assess the use of LLT at time of discharge in patients admitted with ACS along with patient and hospital characteristics associated with American Heart Journal Volume 160, Number 6 use of LLT. This study analyzed data from the hospitals participating in AHA's GWTG-CAD program from 2005 to 2009. Temporal trends in use of LLT were also assessed. In patients admitted with ACS, prescription of various LLTs (various agents and their prescribed doses) at time of the hospital discharge was also assessed in relation to the patients' admission lipid profile with the probability of achieving LDL goal of b100 mg/dL and LDL b70 mg/dL. Methods GWTG-CAD is a national initiative of the AHA to promote guidelines adherence in management of hospitalized patients with coronary artery disease. The data collection process used in this study and quality control features have been previously described.12 All participating institutions were granted waiver of informed consent by their local institutional review boards. The Duke Clinical Research Institute (Durham, NC) serves as the data analysis center and has an agreement to analyze the aggregate de-identified data for research purposes. The GTWG program is supported by the American Heart Association in part through an unrestricted education grant from the Merck Schering Plough Partnership that did not participate in the design, analysis, preparation, review, or approval of the manuscript. The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the paper and its final contents. Study population This study was drawn from 159,713 admissions with the diagnosis of ACS (including ST-segment elevation myocardial infarction [STEMI], non-STEMI [NSTEMI], and unstable angina), between July 2005 and December 2009, from 410 participating hospitals across the United States. Patients were excluded if they left against medical advice, discontinued care, died, or were discharged to a federal hospital, hospice, or another acute care hospital. Of the 138,216 patients discharged, 119,387 (86.4%) were receiving LLT and 14,279 (10.3%) were discharged without LLT. Lipid-lowering therapy was contraindicated in 4,550 (3.3%). Of patients discharged on LLT, 53,991 admissions were also excluded because the details describing agent/dose was missing. The data from 65,396 admissions at 344 sites were complete for the purposes of this analysis and formed the final study population. Appendix Table 1A (online) shows the characteristics of patients included and excluded from the study population. Lipid-lowering therapy Lipid-lowering therapy was defined as therapy likely to achieve a b50% reduction in LLT and included atorvastation 40 or 80 mg, rosuvastatin 20 or 40 mg, simvastatin 80 mg, or any statin of any dose used in combination with ezetimibe (statin/ ezetimibe). All other LLTs were considered as less intensive (LLLT). A secondary analysis excluding ezetimibe and statin combination was performed to assess use and trends in intensive statin monotherapy. Data collected included patient demographics, pertinent medical history, symptoms on arrival, laboratory results, inhospital treatment and procedures, discharge treatment, risk Javed et al 1131 factor counseling, and patient disposition. The lipid levels obtained within the first 24 hours of hospitalization were measured at the local hospital laboratory. Yearly trends in admission lipid values and LLT were assessed from 2005 to 2009. Statistical analysis Patients were divided into the LLT and LLLT categories as defined above. In addition, LLT rate were noted in various subgroups based on admission LDL and high-density lipoprotein (HDL). In the descriptive analysis, the mean (±SD) and percentages were reported for continuous and categorical variables, respectively. For comparison of baseline characteristics in LLT and LLLT groups, Wilcoxon rank-sum tests were used for continuous variables and χ2 tests for categorical variables. In examining the association between LDL and LLT, a multivariable logistic regression was used. The generalized estimating equation (GEE) method with exchangeable working correlation structure was used to account for within-hospital clustering because patients at the same hospital are more likely to have similar responses relative to patients in other hospitals (ie, within-center correlation for response). The method produces estimates similar to those from ordinary logistic regression, but the estimated variances of the estimates are adjusted for the correlation of outcomes within each hospital. The variables entered into the model are patient age, gender, race, body mass index, cardiovascular risk factors (smoking, hypertension, hyperlipidemia, diabetes mellitus, renal insufficiency, prior MI stroke, heart failure, LLT before admission), and type of ACS. A sensitivity analysis (28,724 subjects at 76 sites), confined to the centers with N70% statin medication dose reporting compliance, was used to exclude any selection bias in the primary analysis. A P value of b.05 was considered significant for the test of each variable. All analyses were performed using SAS software (version 9.2, SAS Institute, Cary, NC) by the Duke Clinical Research Institute (Durham, NC). Results The clinical characteristics of the patient study population are shown in Table I. Admission diagnosis was MI in 91.7% patients, while the remaining patients had unstable angina. There were 41.7% of patients who were receiving LLT before the index ACS admission. Admission LDL levels were assessed in 54,892 (83.9%) of patients. The characteristics of patients with and without LDL levels assessed are shown in Appendix Table 1B (online). Patients without lipid testing during hospitalization were more likely to have been receiving LLT before admission. At hospital discharge, there were 25,036 (38.3%) patients receiving LLT and 40,360 (61.7%) receiving LLLT. Patients receiving LLT were younger, less likely to be female, and had higher admission LDL levels (Table I). There were 30.0% of patients who received statin monotherapy, whereas 8.2% received statin/ezetimibe. The characteristics of patients receiving statin monotherapy and those receiving statin/ezetimibe combination are shown in Appendix Table 2 (online). Among various statins, the rate of use and dosage of various statins in LLT subgroup are shown in Appendix Table 3 (online). American Heart Journal December 2010 1132 Javed et al Table I. Baseline characteristics in intensive and less intensive LLT groups Patient characteristics Age (y) Female Race/ethnicity White Black Hispanic Asian Diagnosis STEMI/non-STEMI Unstable Angina LLT taken before Admission Prior myocardial infarction Prior stroke Peripheral vascular disease Hypertension Diabetes—IDDM Diabetes—NIDDM Hyperlipidemia Smoking (current or prior 1 y) β-Blockers ACE inhibitors ARBs Aspirin Clopidogrel Warfarin Nitrates Calcium channel blockers Aldosterone blockers Total cholesterol (mg/dL) LDL cholesterol (mg/dL) HDL cholesterol (mg/dL) Triglycerides (mg/dL) Overall (N = 65 396) Intensive LLT (n = 25 036) Less intensive LLT (n = 40 360) P value 64.7 ± 13.9 34.3% 62.6 ± 13.4 32.2% 66.0 ± 14.1 35.6% b.001 b.001 72.3% 7.0% 6.4% 2.8% 71.4% 7.7% 6.2% 2.9% 72.9% 6.5% 6.5% 2.8% b.001 b.001 .149 .220 91.7% 8.3% 41.7% 19.9% 8.2% 8.1% 67.8% 9.3% 15.9% 55.7% 33.5% 97.7% 72.9% 12.5% 98.2% 80.8% 10.5% 27.0% 9.0% 3.6% 170.1 ± 48.2 103.4 ± 40.0 38.1 ± 12.4 155.4 ± 124.7 92.4% 7.6% 44.4% 21.0% 7.5% 8.0% 67.5% 9.9% 15.9% 58.7% 35.8% 98.1% 75.5% 12.4% 98.6% 84.9% 10.2% 27.8% 8.4% 3.8% 174.6 ± 51.0 107.2 ± 43.0 37.9 ± 11.9 161.0 ± 128.1 91.4% 8.6% 40.0% 19.2% 8.6% 8.2% 67.9% 8.9% 15.9% 53.7% 32.0% 97.4% 71.2% 12.5% 98.0% 78.3% 10.6% 26.6% 9.4% 3.5% 167.1 ± 46.2 101.0 ± 37.7 38.3 ± 12.7 151.8 ± 122.3 b.001 b.001 b.001 b.001 b.001 .341 .319 b.001 .993 b.001 b.001 b.001 b.001 .724 b.001 b.001 .187 b.001 b.001 .066 b.001 b.001 .254 b.001 ARB, Angiotensin receptor blocker; ACE, angiotensin converting enzyme; IDDM, insulin dependent diabetes mellitus; NIDDM, non-insulin dependent diabetes mellitus. Table II. Use of intensive LLT at discharge based on admission HDL-C and LDL-C levels LDL (mg/dL) HDL (mg/dL) b40 (n = 27 762) 40-60 (n = 14 589) ≥60 (n = 2 737) Total (n = 45 088) <70 (n = 9 157) 70-100 (n = 13 603) 100-130 (n = 11 918) 130-160 (n = 6 672) ≥160 (n=3 738) Total (n = 45 088) 13.29% 38.19% 5.70% 36.95% 1.31% 33.45% 20.31% 37.53% 18.71% 36.03% 9.55% 35.53% 1.92% 30.44% 30.17% 35.51% 16.15% 38.68% 8.73% 37.68% 1.56% 34.33% 26.43% 38.09% 8.76% 44.14% 5.28% 43.32% 0.76% 38.71% 14.80% 43.57% 4.66% 52.38% 3.10% 52.58% 0.53% 44.96% 8.29% 51.98% 61.57% 39.58% 32.36% 39.26% 6.07% 34.38% 100% 39.16% Frequency missing 20,308. Numbers in bold denote the percentage of ACS hospitalizations in that cell that received intensive LLT at hospital discharge. When the analysis was confined to 76 hospitals that collected statin dose in N70% of patients (n = 28,724), the findings were similar (39.3% on LLT, of which 33.1% were on statin monotherapy). In comparison, the patients without LLT dose documentation had lower rates of prior LLT, diabetes, hyperlipidemia (lower total cholesterol, LDL cholesterol, and triglycerides), established CAD, prior CABG or percutaneous coronary intervention (PCI), and acute STEMI. These patients however had higher prevalence of hypertension, PVD, prior MI or American Heart Journal Volume 160, Number 6 Figure 1 Javed et al 1133 unstable angina had a lower likelihood of receiving LLT (Figure 1). There was a marginal impact of confining the analysis to intensive statin monotherapy and center reporting compliance on GEE model results. In the statin monotherapy model, diabetes mellitus, prior PCI, and prior CABG were additional independent predictors of LLT. Temporal trends in the use of LLT were also examined. Lipid-lowering therapy rates since the publication of updated National Cholesterol Education Program-ATP guidelines in 2004 increased initially from 35.5% to 41.6% (2005 to 2007). However, an insignificant drop in rate of LLT was noted with a decline to 35.7% by December 2009. We found this to be primarily due to a significant drop in the use of statin/ezetimibe combination from 11.4% in 2007 to 3.4% in 2009 (Table III). When statin/ezetimibe combination was excluded as LLT, less than one third of ACS patients was treated with intensive statin monotherapy. Use of intensive statin monotherapy at discharge was 28.0% in 2005 and 33.1% in 2009, without significant change during the 2007 to 2009 period. Discussion Factors associated with LLT by multivariate GEE model. cerebrovascular accident, and NSTEMI. The excluded sites also had lower rates of revascularization (PCI or CABG) and teaching hospitals. Factors associated with LLT A number of patient characteristics were more frequent in patients discharged with LLT (Table I). Diagnosis of STEMI, presence of ST changes/LBBB on admission ECG, and PCI with or without stent, elevated total cholesterol, LDL, and triglyceride values were more likely to be discharged on LLT. There was no impact of uninsured status, non–insulin-dependent diabetes mellitus, prior CABG, or HDL between the 2 groups. Table II provides the rates of LLT based on admission LDL and HDL levels. Multivariate analysis of these data using the GEE model demonstrated LLT before admission, history of CAD or prior MI, hyperlipidemia, LDL per 10 mg/dL rise, body mass index (BMI) increase by 5 units, PCI with stent placement, and male gender as independent predictors of LLT. Patients with increasing age, chronic dialysis, and The present analysis shows that among hospitals participating in GWTG-CAD, most hospitalized ACS patients are not discharged on LLT. Even among those with admission LDL N130 mg/dL, 50% or less received LLT. During the first 3 years of observation in this study, there was very modest improvement in LLT on discharge. This trend did not persist, instead a decline in this therapeutic approach was observed during 2008 to 2009. Role of intensive LLT in ACS Although statins play a pivotal role in LDL reduction, they may also exhibit a pleotropic effect by decreasing extent of myocardial ischemia, remodeling, as well as promoting plaque stabilization and endothelial function.13-15 Based on these mechanistic properties, and as demonstrated in several clinical studies, it is now widely accepted that initiation of an early and intensive statin therapy in ACS is associated with reduced inpatient mortality and morbidity3,4,6,16 as well as improved longterm survival and lower rates of recurrent coronary events. In the MIRACL trial, LLT with atorvastatin 80 mg/d (vs placebo) was started within 24 to 96 hours of presentation with ACS.6 It was associated with a lower risk of symptomatic ischemia requiring emergent rehospitalization. This effect was independent of baseline LDL level, although LDL was decreased from 126 to 72 mg/dL in the treatment group. The clinical benefit started to exhibit at 4 weeks and then persisted for the duration of the study. The PROVE-IT TIMI 22 trial has further demonstrated that aggressive LLT in ACS, with even lower targets LDL levels, leads to reduction in American Heart Journal December 2010 1134 Javed et al Table III. Temporal trends of intensive LLT and intensive statin monotherapy Year Total (N = 65 396) 2005 2006 2007 2008 2009 5283 15 520 18 082 17 143 9368 Intensive LLT overall (n = 25 036) 1875 6108 7523 6188 3342 (35.49) (39.36) (41.60) (36.10) (35.67) Yearly trend P Intensive statin monotherapy (n = 19 645) .039 .138 b.001 .221 revascularization and unstable angina.3,6 In PROVE-IT TIMI 22, the median LDL was decreased to 62 mg/dL on 80 mg of atorvastatin in comparison to 95 mg/dL on 40 mg of pravastatin. Similar to the findings in the MIRACL, the beneficial effects of high-dose statins emerged as early as 30 days and then persisted during the 2 years of follow-up. Based on the available evidence, the revised Adult Treatment Panel III guidelines has recommended an early and LLT in patients admitted for ACS and has included an optional therapeutic goal of LDL b70 mg/dL in these high-risk patients.8,9 Our analysis shows that despite available evidence and recommendations, in this large cohort of hospitalized patient with ACS, 10.3% (n = 14,279) of patients with ACS were not discharged on LLT. Moreover, only 38.2% of eligible patients were discharged on LLT. Although LDL remains the primary goal for therapeutic intervention, the LLT prescribed at the time of discharge may also take HDL into consideration. The inverse relationship of HDL and with nonfatal MI and cardiovascular-related death has been demonstrated previously.17 The present study illustrates that 61.6% of patients presenting with ACS have HDL levels b40 mg/dL. To improve secondary prevention of cardiovascular risk, it may be necessary to implement additional lipid-modifying therapy (together with routine statin therapy) targeting HDL N40 mg/dL in males and N50 mg/dL in females. Lipid measurement in hospitalized patients with ACS Although the current guidelines recommend lipid measurement in ACS, it is measured in less than half of these patients in routine clinical practice.18 This practice has been largely based on the convention that lipid levels are unreliable in ACS settings and usually associated with an initial decrement in total cholesterol and LDL.19 However, more recent data have shown less pronounced changes in lipid profile.20 In this analysis, about half of ACS patients had LDL b100 mg/dL, with LLT used in about 36% of such patients. Although rate of LLT increased with the rise in LDL, nearly half of patients with LDL N160 mg/dL were still left untreated with LLT. Thus, these patients had a low probability of achieving target LDL in near future. 1422 4516 5467 5220 3020 (26.92) (29.10) (30.23) (30.45) (32.24) Yearly trend P .448 .381 .204 .734 Ezetimibe plus statin (n = 5391) 453 1592 2056 968 322 (8.57) (10.26) (11.37) (5.65) (3.44) Yearly trend P .043 .202 b.001 .002 It is interesting to note that in our study, LLT was more likely to be used in younger patients, male, smokers, overweight patients, in those with STEMI and otherwise those more likely to undergo PCI, and those with high lipid levels. Ironically, patients with diagnosis of unstable angina, prior stroke, heart failure, and renal insufficiency were treated with less LLLT. Moreover, there was no difference in the type of therapy in those with prior CABG and non–insulin-dependent diabetes mellitus. The present study demonstrates the underutilization of LLT in the very high risk group, which is prone to recurrent ischemic cardiovascular events. Lipid-lowering therapy at discharge The available evidence suggests better long-term compliance and higher survival rates in ACS patients initially discharged on statin therapy than those who were not.7 Subsequently, the CRUSADE Quality Improvement Initiative also showed that the use of LLT at discharge among select ACS patients increased from 78% in 2000 to 88% in 2004.21 The overall low rate of LLT observed in our analyses along with recent declines during 2008 to 2009 are concerning and emphasize the need for implementation of evidence-based and guideline-recommended therapy in most patients with ACS. Although intensive statin monotherapy continued to increase marginally, the drop-off in 2008 and 2009 in intensive LLT was essentially due to the decrease in use of ezetimibe in combination in statin therapy. However, there was no offsetting increased use of intensive statin therapy. These data represent interesting, but potentially unfortunate consequences of the well-publicized ENHANCE trial controversy.22-25 In its aftermath, the plethora of discussion raised further controversy about even the proven benefits of statin therapy. This has had a large impact on the contemporary practice of lipid management without providing a clear alternative to the use of ezetimibe. As a result, starting in 2008, fewer ACS patients were treated with therapy that would allow them to achieve LDL cholesterol goals recommended in national guidelines. Despite the lower use of statin/ ezetimibe combination, there was little to no shift to highdose statin therapy (at least at time of hospital discharge). These data underscore yet another impact on routine American Heart Journal Volume 160, Number 6 clinical practice heralded by safety or lack of efficacy concerns as raised by some recent controversies.26,27 Nevertheless, ezetimibe alone or in combination with statin therapy has not been proven to change outcomes in ACS, so the full clinical implications of these treatment shifts are not yet known. Limitations There is a potential for selection bias in this study because discharge LLT dosing data were not available in 50% of patients. There were modest baseline differences between those with and without discharge dosing of lipid therapy recorded. These factors may influence the generalizability of these findings. Furthermore, the GWTG-CAD database is voluntary and therefore may not be representative of the entire US practice. These findings may not reflect care at hospitals that differ substantially from participating hospitals. Registry hospitals tend to be larger than nonparticipating hospitals, are more likely to be affiliated with a medical school, and are more likely to have available facilities for cardiac catheterization, PCI, and cardiac surgery. GWTG-CAD participating hospitals also were provided with feedback on performance that may have also influenced the care patterns. The hospitals participating in the GWTG-CAD program may be more likely to prescribe LLT, such that the treatment gaps are even larger than what was observed here. Hence, the data presented here might reflect different and possibly higher rates of LLT than actually prescribed among patients and hospitals that differ from those participating in GWTG-CAD. Although the lipid levels obtained in this study were measured in the first 24 hours of admission, they may or may not be entirely reflective of the baseline steady-state lipid levels. Furthermore, we do not have data as to whether patients were in the fasting state. This real-world study used results of various commercially available lipid panel assays rather than results from a single central core laboratory. Although this methodology may introduce great variability to lipid testing results, this approach makes these findings more applicable to clinical practice. This study only assessed LLT dosing at time of hospital discharge. Some patients may have had subsequent change in dosing or modification of their lipid therapy regimen as an outpatient. As the current guidelines do not specify a dose of statin for ACS patients but only a target of therapy (ie, optional target of LDL b70 mg/dL in high risk patients), many clinicians may believe that the titration to LLT can occur post discharge, and this may explain the reason for the treatment gap. The utilization of LLT at hospital discharge does not necessarily indicate that patients remained adherent to their discharge regimen. The extent of dietary and exercise counseling were not available in this study. Javed et al 1135 Conclusions During the period of 2005 to 2009, only about one third of patients hospitalized with ACS were discharged on LLT. Even among patients with documented admission LDL, which would require N50% reduction to achieve an optional goal of LDL b70 mg/dL, only about 50% were discharged on LLT. Independent predictors of LLT at discharge included LLT before admission, history of hyperlipidemia or coronary artery disease, increasing BMI and lipid level, and in-hospital percutaneous coronary intervention. In addition, the rate of adopting LLT in ACS decreased significantly over the last 2 years because of a marked decline in the use of ezetimibe in combination with statin therapy without an offsetting increase in intensive statin monotherapy. These findings underscore the importance of ongoing emphasis regarding implementation of current guidelines for measuring lipids and intensive statin therapy in all ACS patients. Disclosures Dr Bhatt: research grants from Astra Zeneca, BristolMyers Squibb, Eisai, Ethicon, Heartscape, Sanofi Aventis and the Medicines Company. Dr Deedwania: consultant/ advisory board of AstraZeneca and Pfizer. Dr Peterson: research funding from Bristol Myers Squibb, Sanofi Aventis partnership. Dr Cannon: research grants from Accumetrics, AstraZeneca, Bristol-Myers Squibb/Sanofi Partnership, Glaxo Smith Kline Intekrin Therapeutics, Novartis, Takeda, clinical advisor and equity in Automedics Medical Systems. Dr Hernandez: research grant from Johnson and Johnson, Merck, and honorarium from AstraZeneca and Medtronic. Dr Fonarow: consultant/ advisory board to Merck Schering Plough and honorarium from Abbott, AstraZeneca, Merck Schering Plough, and Pfizer. Other authors have no disclosures. References 1. Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005;366:1267-78. 2. Blazing MA, De Lemos JA, Dyke CK, et al. The A-to-Z Trial: methods and rationale for a single trial investigating combined use of low-molecular-weight heparin with the glycoprotein IIb/IIIa inhibitor tirofiban and defining the efficacy of early aggressive simvastatin therapy. Am Heart J 2001;142:211-7. 3. Cannon CP, McCabe CH, Belder R, et al. Design of the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE IT)-TIMI 22 trial. Am J Cardiol 2002;89:860-1. 4. de Lemos JA, Blazing MA, Wiviott SD, et al. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. JAMA 2004;292: 1307-16. 5. Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;350:1495-504. 1136 Javed et al 6. Kinlay S, Schwartz GG, Olsson AG, et al. High-dose atorvastatin enhances the decline in inflammatory markers in patients with acute coronary syndromes in the MIRACL study. Circulation 2003;108: 1560-6. 7. Muhlestein JB, Horne BD, Bair TL, et al. Usefulness of in-hospital prescription of statin agents after angiographic diagnosis of coronary artery disease in improving continued compliance and reduced mortality. Am J Cardiol 2001;87:257-61. 8. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Final Report. Circulation 2002;106:3143-421. 9. Grundy SM, Cleeman JI, Merz CNB, et al, for the Coordinating Committee of the National Cholesterol Education Program and Endorsed by the National Heart, Lung, and Blood Institute, American College of Cardiology Foundation, and American Heart Association. Implications of Recent Clinical Trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Circulation 2004;110:227-39. 10. Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction—executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to revise the 1999 guidelines for the management of patients with acute myocardial infarction). J Am Coll Cardiol 2004;44:671-719. 11. Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA 2002 guideline update for the management of patients with unstable angina and non–ST-segment elevation myocardial infarction— summary article. A report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina). J Am Coll Cardiol 2002;40:1366-74. 12. Sachdeva A, Cannon CP, Deedwania PC, et al. Lipid levels in patients hospitalized with coronary artery disease: an analysis of 136,905 hospitalizations in Get With The Guidelines. Am Heart J 2009;157: 111-117.e2. 13. Lefer AM, Campbell B, Shin YK, et al. Simvastatin preserves the ischemic-reperfused myocardium in normocholesterolemic rat hearts. Circulation 1999;100:178-84. 14. Every NR, Frederick PD, Robinson M, et al. A comparison of the national registry of myocardial infarction 2 with the cooperative cardiovascular project. J Am Coll Cardiol 1999;33:1886-94. American Heart Journal December 2010 15. Di Napoli P, Antonio Taccardi A, et al. Simvastatin reduces reperfusion injury by modulating nitric oxide synthase expression: an ex vivo study in isolated working rat hearts. Cardiovasc Res 2001;51: 283-93. 16. Fonarow GC, Wright RS, Spencer FA, et al. Effect of statin use within the first 24 hours of admission for acute myocardial infarction on early morbidity and mortality. Am J Cardiol 2005;96: 611-6. 17. Gordon T, Castelli WP, Hjortland MC, et al. High density lipoprotein as a protective factor against coronary heart disease: The Framingham Study. Am J Med 1977;62:707-14. 18. Ko DT, Alter DA, Newman AM, et al. Association between lipid testing and statin therapy in acute myocardial infarction patients. Am Heart J 2005;150:419-25. 19. Fyfe T, Baxter RH, Cochran KM, et al. Plasma-lipid changes after myocardial infarction. Lancet 1971;2:997-1001. 20. Pitt B, Loscalzo J, Ycas J, et al. Lipid levels after acute coronary syndromes. J Am Coll Cardiol 2008;51:1440-5. 21. Mehta RH, Roe MT, Chen AY, et al. Recent trends in the care of patients with non-ST-segment elevation acute coronary syndromes: insights from the CRUSADE initiative. Arch Intern Med 2006;166: 2027-34. 22. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med 2008;358:1431-43. 23. Carey J. Do cholesterol drugs do any good? Business Week 2008: 52-9. 24. Taubes G. What's cholesterol got to do with it? New York Times 2008. 25. Greenland P, Lloyd-Jones D. Critical Lessons From the ENHANCE Trial. JAMA 2008;299:953-5. 26. Roe MT, Chen AY, Cannon CP, et al. Temporal changes in the use of drug-eluting stents for patients with non–ST-segment–elevation myocardial infarction undergoing percutaneous coronary intervention from 2006 to 2008: results from the Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines (CRUSADE) and Acute Coronary Treatment and Intervention Outcomes Network–Get With The Guidelines (ACTION–GWTG) Registries. Circ Cardiovasc Qual Outcomes 2009;2:414-20. 27. Atwater BD, Oujiri J, Wolff MR. The immediate impact of the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial on the management of stable angina. Clin Cardiol 2009;32:E1-3. American Heart Journal Volume 160, Number 6 Javed et al 1136.e1 Appendix Table 1A. Patient characteristics of the study and excluded patients Patient characteristics Age (y) Female Race/ethnicity White Black Hispanic Asian Diagnosis STEMI/non-STEMI Unstable angina LLT taken before admission Prior myocardial infarction Prior stroke Peripheral vascular disease Hypertension Diabetes—IDDM Diabetes—NIDDM Hyperlipidemia Smoking (current or prior 1 y) β-Blockers ACE inhibitors ARBs Aspirin Clopidogrel Warfarin Nitrates Calcium channel blockers Aldosterone blockers Total cholesterol (mg/dL) LDL cholesterol (mg/dL) HDL cholesterol (mg/dL) Triglycerides (mg/dL) PCI with stent CABG Overall (n = 159 713) Excluded (n = 94 317) Study cohort (N = 65 396) P value 66.2 ± 14.4 35.6% 67.3 ± 14.6 36.5% 64.7 ± 13.9 34.3% b.001 b.001 70.6% 7.4% 5.6% 3.2% 69.4% 7.7% 5.1% 3.5% 72.3% 7.0% 6.4% 2.8% b.001 b.001 b.001 b.001 93.6% 6.4% 94.9% 5.1% 91.7% 8.3% b.001 b.001 20.1% 8.9% 8.7% 68.2% 8.2% 14.1% 51.3% 31.1% 96.9% 70.8% 12.2% 97.4% 75.6% 11.3% 17.8% 6.5% 3.7% 168.7 ± 48.2 102.1 ± 40.0 38.5 ± 12.7 152.9 ± 122.3 35.4% 7.5% 20.4% 9.6% 9.2% 68.6% 7.1% 12.3% 47.2% 29.5% 96.3% 68.8% 12.1% 96.7% 69.9% 12.4% 11.4% 4.7% 3.9% 167.5 ± 48.1 101.1 ± 40.1 38.8 ± 13.1 150.6 ± 120.0 25.1% 6.5% 19.9% 8.2% 8.1% 67.8% 9.3% 15.9% 55.7% 33.5% 97.7% 72.9% 12.5% 98.2% 80.8% 10.5% 27.0% 9.0% 3.6% 170.1 ± 48.2 103.4 ± 40.0 38.1 ± 12.4 155.4 ± 124.7 50.2% 8.7% .042 b.001 b.001 .003 b.001 b.001 b.001 b.001 b.001 b.001 .043 b.001 b.001 b.001 b.001 b.001 .102 b.001 b.001 b.001 b.001 b.001 b.001 ARB, Angiotensin receptor blocker; ACE, angiotensin converting enzyme; IDDM, insulin dependent diabetes mellitus; NIDDM, non-insulin dependent diabetes mellitus. Table 1B. Patient characteristics based on measurement of lipid levels Patient characteristics Overall (N = 65 396) Lipids measured (n = 54 892) Lipids not measured (n = 10 504) P value Age (y) Female Race/ethnicity White Black Hispanic Asian Diagnosis STEMI/non-STEMI Unstable angina LLT taken before Admission Prior myocardial infarction Prior stroke Peripheral vascular disease Hypertension 64.7 ± 13.9 34.3% 64.0 ± 13.8 33.6% 68.4 ± 13.9 38.0% b.001 b.001 72.3% 7.0% 6.4% 2.8% 72.4% 7.1% 6.4% 2.4% 71.9% 6.3% 6.2% 5.0% .290 .002 .427 b.001 91.7% 8.3% 41.7% 19.9% 8.2% 8.1% 67.8% 91.9% 8.1% 38.7% 18.9% 7.7% 7.6% 67.1% 91.1% 8.9% 57.2% 24.9% 10.9% 10.7% 71.4% .008 .008 b.001 b.001 b.001 b.001 b.001 American Heart Journal December 2010 1136.e2 Javed et al Table 1B (continued) Patient characteristics Diabetes—IDDM Diabetes —NIDDM Hyperlipidemia Smoking (current or prior 1 y) β-Blockers ACE inhibitors ARBs Aspirin Clopidogrel Warfarin Nitrates Calcium channel blockers Aldosterone blockers PCI with Stent CABG Intensive LLT Intensive statin monotherapy Statin/ezetimibe Overall (N = 65 396) Lipids measured (n = 54 892) Lipids not measured (n = 10 504) P value 9.3% 15.9% 55.7% 33.5% 97.7% 72.9% 12.5% 98.2% 80.8% 10.5% 27.0% 9.0% 3.6% 50.2% 8.7% 38.3% 30.0% 8.2% 8.4% 15.0% 55.2% 34.9% 97.9% 74.0% 12.0% 98.5% 82.2% 10.4% 26.8% 8.5% 3.4% 52.4% 8.6% 38.9% 30.8% 8.1% 13.7% 20.8% 58.2% 26.2% 96.3% 66.8% 15.1% 97.0% 73.5% 11.0% 28.1% 11.8% 4.7% 38.9% 9.0% 35.2% 26.2% 8.9% b.001 b.001 b.001 b.001 b.001 b.001 b.001 b.001 b.001 .081 .008 b.001 b.001 b.001 .147 b.001 b.001 .004 Table 2. Patient characteristics in intensive LLT groups: overall, statin monotherapy, and ezetimibe plus any statin Patient characteristics Age (y) Female Race/ethnicity White Black Hispanic Asian Diagnosis STEMI/non-STEMI Unstable angina LLT taken before admission Prior myocardial infarction Prior stroke Peripheral vascular disease Hypertension Diabetes—IDDM Diabetes—NIDDM Hyperlipidemia Smoking (current or prior 1 y) Total cholesterol (mg/dL) LDL cholesterol (mg/dL) HDL cholesterol (mg/dL) Triglycerides (mg/dL) Overall LLT (n = 25 036) Statin monotherapy (n = 19 645) Statin/ezetimibe (n = 5 391) P value 62.6 ± 13.4 32.2% 62.4 ± 13.5 31.7% 63.6 ± 12.8 34.0% b.001 .001 71.4% 7.7% 6.2% 2.9% 69.6% 8.1% 6.8% 3.1% 77.9% 6.3% 4.2% 2.2% b.001 b.001 b.001 b.001 92.4% 7.6% 44.4% 21.0% 7.5% 8.0% 67.5% 9.9% 15.9% 58.7% 35.8% 174.6 ± 51.0 107.2 ± 43.0 37.9 ± 11.9 161.0 ± 128.1 93.5% 6.5% 41.3% 19.8% 7.3% 7.4% 66.3% 9.6% 15.6% 55.5% 37.3% 175.6 ± 49.9 108.5 ± 42.5 37.9 ± 11.9 158.8 ± 125.0 88.3% 11.7% 56.0% 25.2% 8.2% 10.0% 71.7% 11.1% 16.8% 70.0% 30.5% 170.8 ± 54.5 102.1 ± 44.6 38.1 ± 11.9 169.4 ± 138.4 b.001 b.001 b.001 b.001 .038 b.001 b.001 .002 .050 b.001 b.001 b.001 b.001 .085 b.001 Table 3. Specific lipid-lowering agents in treatment groups Statin Rosuvastatin Stain dose 5 mg 10 mg 20 mg 40 mg Overall (N = 65 396) 649 2116 1156 417 Overall (%) LLT (n = 25 036) LLT (%) 0.99 3.24 1.77 0.64 31 85 1156 417 0.12 0.34 4.62 1.67 LLLT (n = 40 360) 618 2031 0 0 LLLT (%) 1.53 5.03 0.00 0.00 American Heart Journal Volume 160, Number 6 Javed et al 1136.e3 Table 3 (continued) Statin Atovastatin Simvastatin Simvastatin/ezetimibe Combination Statin/ezetimibe⁎ Stain dose 10 mg 20 mg 40 mg 80 mg 5 mg 10 mg 20 mg 40 mg 80 mg 10-10 mg 10-20 mg 10-40 mg 10-80 mg Other ⁎ Ezetimibe and any dose of any statin in separate doses. Overall (N = 65 396) Overall (%) LLT (n = 25 036) LLT (%) LLLT (n = 40 360) LLLT (%) 4122 5683 7331 7919 94 1086 6665 10 887 3589 153 1005 1815 603 131 1690 6.30 8.69 11.21 12.11 0.14 1.66 10.19 16.65 5.49 0.23 1.54 2.78 0.92 0.20 2.58 52 109 7331 7919 2 24 121 284 3589 153 1005 1815 603 131 1690 0.21 0.44 29.28 31.63 0.01 0.10 0.48 1.13 14.34 0.61 4.01 7.25 2.41 0.52 6.75 4070 5574 0 0 92 1062 6544 10 603 0 0 0 0 0 0 0 10.08 13.81 0.00 0.00 0.23 2.63 16.21 26.27 0.00 0.00 0.00 0.00 0.00 0.00 0.00