Optimizing lipid management in patients with acute coronary syndromes

Optimizing Lipid Management in Patients with Acute Coronary Syndromes Carl J. Pepine,

MD

According to the Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III), patients with low-density lipoprotein (LDL) cholesterol >130 mg/dL should be discharged on lipid-lowering therapy. When LDL cholesterol levels are between 100 and 129 mg/dL, evaluation of ratios of LDL cholesterol/high-density lipoprotein (HDL) cholesterol or total cholesterol/HDL cholesterol may provide additional insight into a patient’s risk status. Patients who were using statin therapy before admission for an acute coronary syndrome should be continued on lipid-lowering therapy. The American College of Cardiology/American Heart Association (ACC/AHA) 2002 guideline update for management of patients with unstable angina and non–ST-seg-

ment elevation myocardial infarction recommends statin therapy at discharge as a class I indication, level of evidence A. Furthermore, studies confirm that statin therapy begun early during hospitalization can prevent ischemic events in patients who are treated by an invasive strategy and those who are treated only by a medical strategy. However, studies suggest that patient compliance with a statin regimen after discharge is far from optimal. There are 2 programs available to help ensure that appropriate patients receive and continue taking lipid-lowering therapy. These programs are the Cardiac Hospitalization Atherosclerosis Management Program (CHAMP) and the Guidelines Applied in Practice (GAP). 䊚2003 by Excerpta Medica, Inc. Am J Cardiol 2003;91(suppl):30B–35B

ebate surrounding treatment of patients with acute coronary syndromes (ACS) has focused on D risk stratification, the role of new antiplatelet and

dence supporting these important new recommendations. This article reviews those studies.

antithrombin agents, and optimal use of conservative and early invasive strategies. However, the substantial database information that has emerged in the past 2 years on the clinical benefits of early statin use in ACS (Table 1)1–18 mandates expansion of this debate to include discussion of evaluation and treatment of lipids during hospitalization for ACS. The Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) took the first step in stating that all patients hospitalized for ACS should have their low-density lipoprotein (LDL) cholesterol levels measured.19 Preferably, this should occur within the first 24 hours. Although there is concern for possible influence of “acute-phase” reactants on lipoprotein levels, a lipoprotein profile taken during hospitalization can provide useful information. Patients with LDL cholesterol levels ⱖ130 mg/dL should be discharged on lipid-lowering therapy.19 Subsequently, the American College of Cardiology/American Heart Association (ACC/AHA) 2002 guideline update for management of patients with unstable angina and non–STsegment elevation myocardial infarction (MI), listed statin therapy at discharge as a class I recommendation (level of evidence A).20 A number of new studies have been published that strengthen and extend our understanding of the evi-

ASSESSING LIPID LEVELS

From the Division of Cardiovascular Medicine, University of Florida College of Medicine, Gainesville, Florida, USA. Address for reprints: Carl J. Pepine, MD, Division of Cardiovascular Medicine, University of Florida College of Medicine, 1600 Archer Road, Gainesville, Florida 32610-0277. E-mail: pepincj@medicine. ufl.edu.

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©2003 by Excerpta Medica, Inc. All rights reserved.

Clinical judgment should be used in deciding whether to initiate drug treatment in patients with LDL cholesterol levels of 100 to 129 mg/dL.19 In such cases, LDL cholesterol/high-density lipoprotein (HDL) cholesterol ratio or total cholesterol/HDL cholesterol ratio may provide additional insight into a patient’s risk status. Wattanasuwan et al21 measured lipid levels in 45 patients admitted for acute MI. Between day 1 and day 4 of the post-MI period, serum levels of total cholesterol, LDL cholesterol, and HDL cholesterol decreased significantly. In particular, LDL cholesterol levels were 120.3 ⫾ 48.9 mg/dL on day 1 and 105.9 ⫾ 43.0 mg/dL on day 4 (p ⫽ 0.009). However, neither LDL cholesterol/HDL cholesterol nor total cholesterol/HDL-C ratios changed significantly (2.96 ⫾ 1.58 vs 2.99 ⫾ 1.44 and 4.59 ⫾ 1.84 vs 4.67 ⫾ 1.77, respectively). Another important consideration is whether a patient’s low lipid levels are a result of prior statin therapy. The Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) study was a comparison of glycoprotein IIb/IIIa inhibition (tirofiban) and unfractionated heparin in 3,232 patients hospitalized with ACS.22 Heeschen et al6 performed a subgroup analysis of 1,616 patients, 465 of whom were taking statins (lovastatin, pravastatin, or simvastatin) before symptom onset. Statin therapy was withdrawn upon hospitalization in 86 (18.5%) of these 465 patients. Similar levels of total cholesterol (approximately 200 mg/dL) were noted in patients whose statin therapy was withdrawn and those whose statin therapy was continued (data on LDL cholesterol levels were not reported). Interestingly, withdrawal of statin ther0002-9149/03/$ – see front matter doi:10.1016/S0002-9149(02)03290-3

TABLE 1 Studies of Early Statin Use in Acute Coronary Syndromes (ACS) Study

N

Treatment

AMI AMI ACS/SA UA/AMI/IHF

19,599 8,335 600 558

Combined databases of GUSTO and PURSUIT5† PRISM6† SYMPHONY and SYMPHONY 27†

ACS

20,809

Statins Statins Statins Statins/aspirin/ACE inhibitors/ ␤-blockers Lipid-lowering agents (principally statins)

ACS ACS

1,616 12,365

Walter et al8 Chan et al9 Moscucci et al10 Giugliano et al11†

ACS Scheduled/elective PCI Scheduled/elective PCI STEMI

704 5,052 16,932 14,124

Observational data (nonrandomized)* RIKS-HIA1 MITRA2 LDS Hospital3 CHAMP4

Randomized trials* L-CAD12 MIRACL13 FLORIDA14 LIPS15 Kayikcioglu et al16 A to Z17‡ PROVE IT18‡

Population

ACS UA/NSTEMI STEMI Stable angina/unstable angina/ silent ischemia STEMI ACS UA/NSTEMI

Statins Statins/aspirin/oral GPIIb/IIIa inhibitor Statins Statins Statins Lipid-lowering agents (principally statins) ⫹ thrombolytics

135 3,086 540 1,677

Pravastatin ⫾ niacin/cholestyramine Atorvastatin Fluvastatin Fluvastatin

164 4,500 4,000

Pravastatin ⫹ thrombolytics Simvastatin Atorvastatin or pravastatin

A to Z ⫽ Aggrastat to Zocor; AMI ⫽ acute myocardial infarction; CHAMP ⫽ Cardiac Hospital Atherosclerosis Management Program; FLORIDA ⫽ Fluvastatin on Risk Diminishing After Myocardial Infarction; GPIIb/IIIa ⫽ glycoprotein IIb/IIIa receptor; IHF ⫽ ischemic heart failure; GUSTO ⫽ Global Use of Streptokinase or t-PA for Occluded Coronary Arteries; L-CAD ⫽ Lipid-Coronary Artery Disease study; LIPS ⫽ Lescol Intervention Prevention Study; MIRACL ⫽ Myocardial Ischemia Reduction in Aggressive Cholesterol Lowering; MITRA ⫽ Maximal Individual Therapy in AMI; NSTEMI ⫽ non–ST-segment elevation myocardial infarction; PCI ⫽ percutaneous coronary intervention; PRISM ⫽ Platelet Receptor Inhibition for Ischemic Syndrome Management; PROVE IT ⫽ Pravastatin or Atorvastatin Evaluation and Infection Therapy; PURSUIT ⫽ Platelet Glycoprotein IIb/IIIa in Unstable Angina Receptor Suppression Using Integrilin Therapy; RIKS-HIA ⫽ Swedish Register of Cardiac Intensive Care; SA ⫽ stable angina; STEMI ⫽ ST-elevation myocardial infarction; SYMPHONY ⫽ Sibrafibran Versus Aspirin to Yield Maximum Protection from Ischemic Heart Events Post-Acute Coronary Syndromes; UA ⫽ unstable angina. *All completed studies reported improved outcomes with statin use, with the exception of Newby et al7, which reported a neutral effect. † Retrospective subgroup analysis. ‡ Ongoing.

apy was associated with an approximate tripling in risk of cardiac events compared with patients who continued to receive statins (hazard ratio, 2.93; 95% confidence interval [CI], 1.64 to 6.27; p ⫽ 0.005). Correia et al23 addressed the issue of what happens to lipid levels during the “acute phase” of an ACS in hospitalized patients who are treated with statins. In all, 56 patients presenting with non–ST-segment elevation ACS with onset in the previous 48 hours were randomized to receive either atorvastatin 80 mg or placebo. Patients in both groups were treated to a similar extent with combinations of antiplatelet agents, low-molecularweight heparins, angiotensin-converting enzyme inhibitors, ␤-blockers, nitrates, and glycoprotein IIb/IIIa inhibitors. Results are shown in Figure 1. After 5 days, significant reductions from baseline in total cholesterol (⫺44 ⫾ 20 mg/dL, p ⬍0.01), and LDL cholesterol (⫺37 ⫾ 23 mg/dL, p ⬍0.001) were observed in the atorvastatin-assigned group. In the placebo-assigned group, levels of total cholesterol and LDL cholesterol trended downward and triglycerides trended upward; in the atorvastatin group triglycerides trended downward, although none of these trends in the 2 groups were significantly different from baseline. HDL cholesterol levels were significantly reduced from baseline in the atorvastatin group (⫺3.7 ⫾ 7.7 mg/dL, p ⫽ 0.012) but not the

placebo group (⫺0.96 ⫾ 1.6 mg/dL). However, the LDL cholesterol/HDL cholesterol ratio decreased significantly in the atorvastatin group (⫺0.3 ⫾ 1.3, p ⬍0.001), indicating an overall favorable change in the lipid profile during this brief period. In addition, the Myocardial Ischemia Reduction with Aggressive Lipid Lowering (MIRACL) study, which was also conducted with atorvastatin 80 mg versus placebo in patients with non–ST-segment elevation ACS, found that HDL cholesterol was reduced nonsignificantly at 6 weeks but that levels had increased to slightly above baseline at 16 weeks. In contrast, levels of total cholesterol and LDL cholesterol were significantly reduced at both 6 and 16 weeks.13 These findings demonstrate that statin therapy is associated with significant reductions in levels of total cholesterol and LDL cholesterol beyond that routinely observed during the acute phase of MI, and that these reductions are maintained with continued therapy. Reductions in HDL cholesterol that may occur are small and transient.

ROLE OF LIPID LOWERING IN PATIENTS TREATED BY AN INVASIVE STRATEGY The MIRACL study excluded patients for whom percutaneous coronary intervention (PCI) was schedSTATINS AND THE VASCULAR WALL

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FIGURE 1. Effects of statin (atorvastatin 80 mg) and placebo on serum lipids during the acute phase of unstable angina/non–ST-segment elevation myocardial infarction. Therapy was begun within 48 hours of symptom onset and continued for 5 days. The statin produced significant reductions in total cholesterol (total-C) and low-density lipoprotein cholesterol (LDL-C) beyond the reduction associated with the ischemic syndrome. HDL-C ⴝ high-density lipoprotein cholesterol. (Reproduced with permission from Am J Cardiol.23)

uled or anticipated in the near term, to avoid possible confounding by events related to either restenosis of the target lesion or repeated invasive procedures.13 Subsequent studies, however, show that statin therapy can provide clinical benefit in these patients. This provides further evidence that atherosclerosis is a diffuse disease with sites of potentially unstable lesions located throughout the coronary vascular bed, which can be modified with statins. The Lescol Intervention Prevention Study (LIPS) enrolled 1,677 patients with a broad range of total cholesterol levels (135 to 270 mg/dL) who were scheduled for a first PCI procedure for stable/unstable angina or silent ischemia.15 At an average of 2.7 days after the procedure, subjects were randomly assigned to either a statin (fluvastatin 40 mg twice daily) or placebo. The primary outcome was time to first major adverse cardiac event, which included cardiac death, nonfatal MI, or repeat revascularization. Event-time plots for those assigned statin and placebo started to diverge after approximately 1.5 years. At the end of the study (3.9 years median follow-up time), an event in the primary outcome cluster had occurred in 21.4% and 26.7% of the statin and placebo groups, respectively (relative risk, 0.78; 95% confidence interval, 0.64 to 0.95; p ⫽ 0.01; Figure 2). Consistent benefit was also demonstrated in the secondary outcomes, including cardiac death, noncardiac death, all-cause death, cardiac death/MI, all-cause death/MI, and major adverse cardiac event other than restenosis. LIPS provides the first prospective clinical evidence that statin therapy is safe and effective in reducing coro32B THE AMERICAN JOURNAL OF CARDIOLOGY姞

nary ischemic events in patients who have undergone PCI. Greater reduction in risk of the primary outcome was achieved in patients (1) with multivessel versus single-vessel disease, (2) with diabetes versus without diabetes, and (3) undergoing PCI without stenting versus with stenting.11 However, the point estimation for risk reduction in patients with levels of total cholesterol or LDL cholesterol below the median baseline level of 132 mg/dL was comparable to that achieved in patients with baseline LDL cholesterol above the median, although neither achieved statistical significance because of the wide confidence intervals (Figure 3). Comparable risk reduction trends were also observed in patients without prior MI versus with prior MI, and stable angina versus unstable angina. Walter et al8 reported on 704 consecutive patients who underwent successful stent implantation between 1997 and 1999. The study population included 335 patients with chronic stable angina, 224 with unstable angina, and 145 with Q-wave MI. Statin therapy (atorvastatin, fluvastatin, lovastatin, or simvastatin) was initiated 24 hours after PCI in all patients in whom LDL cholesterol levels were ⬎75th percentile, adjusted for age and sex. Many patients also received aspirin, ␤-blockade, and angiotensin-converting enzyme inhibitors. Statin treatment was associated with reduced risk of cardiac death or nonfatal MI in the stable angina and unstable angina groups but not in the Q-wave MI group. For example, compared with patients with stable angina who received statins, there was a ⬎4-fold increased risk in patients with unstable

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FIGURE 2. Major adverse cardiac event (MACE)–free survival time in patients receiving statin (fluvastatin) or placebo after percutaneous intervention in the Lescol Intervention Prevention Study (LIPS). (MACE includes cardiac death, nonfatal myocardial infarction, or repeat revascularization). (Reproduced with permission from JAMA.15)

FIGURE 3. Relative risk of a major adverse cardiac event (cardiac death, nonfatal myocardial infarction, or repeat revascularization) in subgroups classified according to baseline cholesterol level in the Lescol Intervention Prevention Study (LIPS). Baseline median total cholesterol (Total-C) level ⴝ 200 mg/dL. Baseline median low-density lipoprotein cholesterol (LDL-C) level ⴝ 132 mg/dL. CI ⴝ confidence interval; HDL-C ⴝ high-density lipoprotein cholesterol. (Reproduced with permission from JAMA.15)

angina who did not receive statins (odds ratio, 6.9; 95% CI, 1.5 to 31; p ⫽ 0.004), but this risk was substantially reduced in patients with unstable angina who received statins (odds ratio, 1.5; 95% CI 0.2 to 11; p ⫽ 0.7). The beneficial effects of statin treatment appeared to be most prominent during the first 4 weeks. Chan et al9 reported data from an observational study of 5,052 patients who underwent PCI between 1993 and 1999. The 30-day mortality was 0.8% in patients treated with statins before the procedure and 1.5% in those who were not treated with statins (hazard ratio, 0.53; p ⫽ 0.048). This difference in mortality was sustained at 6 months (2.4% vs 3.6%; hazard ratio, 0.67; p ⫽ 0.046). Moscucci et al10 reported data from an observational

study of 9,084 patients who were using statin therapy before PCI and 7,848 patients who were not using statin therapy. Data represented procedures conducted between July 1997 and September 2000. In-hospital mortality rates were 0.58% in the statin-pretreatment group and 2.8% in the control group (odds ratio, 0.2; 95% CI, 0.14 to 0.24; p ⬍0.001).

ROLE OF LIPID LOWERING IN PATIENTS RECEIVING THROMBOLYTIC THERAPY The Intravenous nPA for the Treatment of Infarcting Myocardium Early (InTIME) II trial compared effects of thrombolytic agents (lanoteplase and alteplase) in patients with ST-elevation MI.24 Giugliano et STATINS AND THE VASCULAR WALL

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al11 reported on 14,124 patients who survived the index event. Initiation or continuation of lipid-lowering therapy during hospitalization was associated with a 33% reduction in 1-year mortality (p ⫽ 0.00005). There was a nonsignificant trend toward greater risk for 1-year mortality in patients whose lipid-lowering therapy was discontinued during hospitalization (odds ratio, 1.05; 95% CI, 0.61 to 1.83; p ⫽ 0.86). Kayikcioglu et al16 reported on an open-label, single-center study of 164 patients with ST-elevation MI who were randomly assigned within 6 hours of admission to receive either pravastatin 40 mg or no lipid-lowering therapy. The 6-month incidence of cardiovascular events (principally angina) was 30% and 59% in the statin and control groups, respectively (p ⫽ 0.02).

TABLE 2 Guidelines in Clinical Practice (GAP) Tool Kit for Medical Professionals ● ● ● ● ● ● ●

Acute MI standing orders Clinical pathway Summary of ACC/AHA acute MI guidelines in pocket-size format Patient information form Patient discharge form Chart stickers Hospital performance charts

ACC ⫽ American College of Cardiology; AHA ⫽ American Heart Association; MI ⫽ myocardiol infarction. Adapted from JAMA.27

with follow-up visits at 6 and 12 months to monitor lipids and encourage compliance. The Guidelines Applied in Practice (GAP) initiative:

REALIZING THE POTENTIAL OF STATINS Jackevicius et al25 assessed compliance with statin therapy in 3 cohorts of patients ⱖ66 years of age: (1) those with recent ACS (n ⫽ 22,379), (2) those with chronic coronary artery disease (n ⫽ 36,106), and (3) those without coronary artery disease (n ⫽ 85,020). Adherence to statin therapy was defined as having a statin prescription dispensed at least every 120 days after the initial prescription date until the end of a 2-year follow-up period. Adherence rates were 40.1% (ACS cohort), 36.1% (chronic coronary artery disease cohort), and 25.4% (primary prevention cohort). The primary prevention cohort was almost twice as likely as the ACS cohort to be noncompliant (relative risk, 1.92; 95% CI, 1.87 to 1.96). These data support the findings of a previous study3 that patients hospitalized for ACS are more motivated to adhere to a risk factor reduction program than are primary prevention patients. However, they also suggest that good compliance with statin therapy is not a given, even in ACS patients. Recently, 2 quality initiatives were published. Both have resulted in significantly increased use of statins, as well as aspirin, ␤-blockers, and angiotensin-converting enzyme inhibitors.26,27 The Cardiac Hospitalization Atherosclerosis Management Program (CHAMP): CHAMP was developed at a

university-associated teaching hospital.26 Targeted patients include those hospitalized with unstable angina, acute MI, ischemic heart failure, and those scheduled for coronary catheterization and revascularization procedures. A treatment algorithm was developed that specifies a full lipid panel and liver function tests on admission and provides recommendations for initiation of aspirin, ␤-blockers, angiotensin-converting enzyme inhibitors, and statins. If a baseline lipid panel is not obtained or obtained ⬎12 hours after onset of MI, statin therapy was initiated and dosed empirically. Predischarge counseling on smoking cessation, diet, and exercise is conducted by individual physicians and cardiac nurses, using patient education materials developed for the program. The algorithm recommends a lipid panel and liver function tests at 6 weeks, 34B THE AMERICAN JOURNAL OF CARDIOLOGY姞

GAP is an ACC initiative developed in collaboration with the Michigan Peer Review Organization and the Southeast Michigan Quality Forum for Cardiovascular Care (under the auspices of the Greater Detroit Area Health Council).27 Representatives from each of these organizations formed a core team that established performance indicators and developed a “tool kit” designed to facilitate adherence to key quality indicators (Table 2). This tool kit can be subsequently customized by participating hospitals. Members of the core team also identified local physician and nurse opinion leaders and worked with these individuals to implement the GAP program. The ACC, the AHA, and the National Heart, Lung, and Blood Institute have jointly issued a clinical advisory on the use and safety of statins.28 The advisory provides criteria for identifying patients who may be at increased risk of myopathy and recommendations on monitoring and other clinical steps to avoid this rare side effect and to help keep patients taking these important drugs.

CONCLUSIONS Early, intensive lipid-lowering therapy with statins should be administered to ACS patients who do not have contraindications. Treatment should be initiated in the hospital, regardless of baseline LDL cholesterol levels, which may be confounded by the acute phase reaction. LDL cholesterol levels can be used to titrate statin doses. Trials now in progress should help to better define possible subgroups that may obtain greater or lesser benefit.17,18 1. Stenestrand U, Wallentin L, for the Swedish Register of Cardiac Intensive Care (RIKS-HIA). Early statin treatment following acute myocardial infarction and 1-year survival. JAMA 2001;285:430 –436. 2. Schiele R, Gitt AK, Heer T, Wienbergen H, Gieseler U, Glunz HG, Senges J. Early statin use in acute myocardial infarction is associated with a reduced hospital mortality: results of MITRA-2. Circulation 2000;102:II-435. Abstract 2117. 3. Muhlestein JB, Horne BD, Bair TL, Li Q, Madsen TE, Pearson RR, Anderson JL. 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;87:257–261. 4. Fonarow GC, Gawlinski A, Moughrabi S, Tillisch JH. Improved treatment of coronary heart disease by implementation of a cardiac hospitalization atherosclerosis management program (CHAMP). Am J Cardiol 2001;87:819 –822.

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5. Aronow HD, Topol EJ, Roe MT, Houghtaling PL, Wolski KE, Lincoff AM, Harrington RA, Califf RM, Ohman EM, Kleiman NS, et al. Effect of lipidlowering therapy on early mortality after acute coronary syndromes: an observational study. Lancet 2001;357:1063–1068. 6. Heeschen C, Hamm CW, Laufs U, Snapinn S, Bo¨ hm M, White HD, on behalf of the Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) Investigators. Withdrawal of statins increases event rates in patients with acute coronary syndromes. Circulation 2002;105:1446 –1452. 7. Newby LK, Kristinsson A, Bhapkar MV, Aylward PE, Dimas AP, Klein WW, McGuire DK, Moliterno DJ, Verheugt FWA, Weaver WD, Califf RM. Early statin initiation and outcomes in patients with acute coronary syndromes. JAMA 2002;287:3087–3095. 8. Walter DH, Fichtlscherer S, Britten MB, Auch-Schwelk W, Scha¨ chinger V, Zeiher AM. Benefits of immediate initiation of statin therapy following successful coronary stent implantation in patients with stable and unstable angina pectoris and Q-wave myocardial infarction. Am J Cardiol 2002;89:1–6. 9. Chan AW, Bhatt DL, Chew DP, Quinn MJ, Moliterno DJ, Topol EJ, Ellis SG. Early and sustained survival benefit associated with statin therapy at the time of percutaneous coronary intervention. Circulation 2002;105:691–696. 10. Moscucci M, Kline-Rogers E, DeFranco AC, O’Donnell M, Maxwell-Eward A, Share D, McGinnity JG, De Gregorio M, Meengs WL, Clark VL, Eagle KA, for the Blue Cross Blue Shield of Michigan Cardiovascular Consortium (BMC2). Effects of pre-procedure lipid lowering therapy on in-hospital mortality following percutaneous coronary interventions: an analysis of a large multicenter database. J Am Coll Cardiol 2002;39(32A):32A. Abstract 1102–1125. 11. Giugliano RP, Antman EM, Thompson SL, McCabe CH, Braunwald E. Lipid lowering drug therapy initiated during hospitalization for acute MI is associated with lower postdischarge 1-year mortality. J Am Coll Cardiol 2001;37:316A. Abstract 1053-91. 12. Arntz H-R, Agrawal R, Wunderlich W, Schnitzer L, Stern R, Fischer F, Schultheiss H-P. Beneficial effects of pravastatin (⫾ colestyramine/niacin) initiated immediately after a coronary event (the Randomized Lipid-Coronary Artery Disease study [L-CAD]). Am J Cardiol 2000;86:1293–1298 13. Schwartz GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, Waters D, Zeiher A, Chaitman BR, Leslie S, Stern T, for the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study Investigators. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA 2001;285: 1711–1718. 14. Liem A, van Boven AJ, Withagen AP, de Medina RMR, Veeger NJGM, Tijssen JGP. Fluvastatin in acute myocardial infarction: effects on early and late ischemia and events: the FLORIDA trial [abstract]. Circulation 2000;102:2672-d. 15. Serruys PWJC, de Feyter P, Macaya C, Kokott N, Puel J, Vrolix M, Branzi A, Bertolami MC, Jackson G, Strauss B, Meier B, for the Lescol Intervention Prevention Study (LIPS) Investigators. Fluvastatin for prevention of cardiac events following successful first percutaneous coronary intervention: a randomized controlled trial. JAMA 2002;287:3215–3222. 16. Kayikcioglu M, Turkoglu C, Can L, Pazin S, Kultursay H. The combined use of pravastatin with thrombolytic agents in acute myocardial infarction: results of

clinical and angiographic follow-up. J Am Coll Cardiol 2000;35:345A. Abstract 1038-130. 17. Blazing MA, De Lemos JA, Dyke CK, Califf RM, Bilheimer D, Braunwald E. The A-to-Z trial: methods and rationale for a single trial investigating combined use of a low-molecular-weight heparin with the glycoprotein IIb/IIIa inhibitor tirofiban and defining the efficacy of an early aggressive simvastatin therapy. Am Heart J 2001;142:211–217. 18. Cannon CP, McCabe CH, Belder R, Breen J, Braunwald E. Pravastatin or atorvastatin evaluation and infection therapy (PROVE IT)-TIMI 22 Trial: rationale and design. Am J Cardiol 2002;889:860 –861. 19. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. 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). Available at: http://www. nhlbi.nih.gov/guidelines/cholesterol/atp3_rpt.pdf. Accessed July 2002. 20. Braunwald E, Antman EM, Beasley JW, Califf RM, Cheitlin MD, Hochman JS, Jones RH, Keriakes D, Kupersmith J, Levin TN, et al. ACC/AHA guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (Committee on the Management of Unstable Angina) 2002. Available at: http://www.acc.org/ clinical/guidelines/unstable/unstable.pdf. Accessed May 2002. 21. Wattanuasuwan N, Khan IA, Gowda RM, Vasavada BC, Sacchi TJ. Effect of acute myocardial infarction on cholesterol ratios. Chest 2001;120:1196 –1199. 22. The Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) Study Investigators. A comparison of aspirin plus tirofiban with aspirin plus heparin for unstable angina. N Engl J Med 1998;338:1498 –1505. 23. Correia LCL, Spo´ sito AC, Passos LCS, Lima JC, Braga JC, Rocha MS, Esteves JP, D’Oliveira A. Short-term effect of atorvastatin (80 mg) on plasma lipids of patients with unstable angina pectoris or non-Q-wave acute myocardial infarction. Am J Cardiol 2002;90:162–164. 24. The InTIME II Investigators. Intravenous NPA for the treatment of infarcting myocardium early: InTIME II, a double-blind comparison of single-bolus lanoteplase vs accelerated alteplase for the treatment of patients with acute myocardial infarction. Eur Heart J 2000;21:2005–2013. 25. Jackevicius CA, Mamdani M, Tu JV. Adherence with statin therapy in elderly patients with and without acute coronary syndromes. JAMA 2002;288:462–467. 26. Fonarow GC, Gawlinski A, Moughrabi S, Tillisch JH. Improved treatment of coronary heart disease by implementation of a Cardiac Hospitalization Atherosclerosis Management Program (CHAMP). Am J Cardiol 2001;87:819 –822. 27. Mehta RH, Montoye CK, Gallogly M, Baker P, Blount A, Faul J, Roychoudhury C, Borzak S, Fox S, Franklin M, et al, for the GAP Steering Committee of the American College of Cardiology. Improving quality of care for acute myocardial infarction: the Guidelines Applied in Practice (GAP) Initiative. JAMA 2002;287:1269 –1276. 28. Pasternack RC, Smith SC Jr, Bairey-Merz CN, Grundy SM, Cleeman JI, Lenfant C. ACC/AHA/NHLBI clinical advisory on the use and safety of statins. J Am Coll Cardiol 2002;40:568 –573.

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