Routine statin treatment after acute coronary syndromes?

Editorial

Routine statin treatment after acute coronary syndromes? Monica Acevedo, MD, Dennis L. Sprecher, MD, Michael S. Lauer, MD, and Gary Francis, MD Cleveland, Ohio

HMG CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors are profoundly underused in secondary prevention subjects.1-3 Pathways to improve usage of these agents are imperative. Two recent studies4,5 demonstrated that the initiation of statin therapy in patients at the time of hospital discharge at least doubled statin usage rates, resulting in a reduction in short-term mortality. The recently released Adult Treatment Panel guidelines (ATP III)6 have reemphasized the importance of lipid lowering at hospital discharge for continued compliance. This has become particularly compelling in the subset of hospitalized patients with acute coronary syndromes (ACS), in which a currently evolving series of reports have suggested universal statin use as particularly protective.7-11 The ATP guidelines currently mandate low-density lipoprotein cholesterol (LDL-C) testing with values ⬎130 mg/dL or, optionally, ⬎100 mg/dL before statin initiation. This recommendation represents a trade-off between operational and preventive benefits of universal statin use after ACS and the lack of clear evidence for statin-induced cardiovascular protection in patients with low baseline LDL-C values. This latter concern has been lessened recently by the results from the Heart Protection Study, in which statin-related protection from cardiovascular events was observed in patients at high risk with LDL ⬍100 mg/dL (AHA presentation, 2001).12 The prevalence of LDL-C testing within the narrow first–24-hour window of the event (a unique interval that continues to reflect steady-state lipid levels13-15) is quite low5,16,17 and out of step with current national recommendations. We believe that this guideline-based decision on statin therapy after ACS merits further review. Perhaps it is time to allow statins to travel the aspirin pathway in patients after ACS. Two series of reports in the literature recommending continued or initial use of statins are persuasive. First, introduction of statin use in the acute setting in which

From the Department of Cardiology and Section of Preventive Cardiology and Cardiac Rehabilitation, The Cleveland Clinic Foundation, Cleveland, Ohio. Reprint requests: Dennis L. Sprecher, MD, Section Head, Preventive Cardiology and Rehabilitation, Department of Cardiology, C51, The Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, Ohio 44195. E-mail: [email protected] Am Heart J 2002;143:940-2. © 2002, Mosby, Inc. All rights reserved. 0002-8703/2002/$35.00 ⫹ 0 4/4/122284 doi:10.1067/mhj.2002.122284

thrombosis, inflammation, and vasoconstriction more critically define outcomes may be particularly valuable. Investigators from the recent Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering Study (MIRACL) trial7 randomly assigned patients to receive 80 mg of atorvastatin or placebo within the first 24 to 96 hours of a non–Q-wave myocardial infarction (MI) (54%) or unstable angina (46%). A total of 3806 patients at high risk were observed for 4 months, incurring an LDL-C decrease of 40% (124-72 mg/dL). Although more patients receiving atorvastatin developed liver enzyme elevations (2.5% vs 0.6%, treatment vs placebo group), overall serious adverse events were rare and equivalent between groups (⬍1% in both). At the 16-week follow-up observation, there was a 16% reduction (relative risk ratio ⫽ 0.84, 95% CI 0.7-1.0, P ⫽ .048) in the combined primary end point of death, nonfatal acute MI, cardiac arrest, or worsening angina with hospitalization in the treatment group (14.8% vs 17.4% in the placebo group). Further, LDL-C lowering did not correlate with these outcomes, suggesting nontraditional benefits from the statin agent. These could include a decrease in thrombus formation,18 improved fibrinolysis,18 and both inhibition of thromboxane A2 biosynthesis and platelet function,19 reported to be apparent within 3 months of statin initiation. Data from small observational studies also suggest early benefits from statin therapy initiated in the coronary care unit. The combined benefits of pravastatin plus thrombolytic therapy versus thrombolytic therapy alone provided during the first 6 hours of the onset of chest pain in 150 patients significantly reduced inhospital death and nonfatal reinfarction at 6 months (P ⫽ .03 and P ⫽ .01, respectively).9 In a separate study, pravastatin provided within 6 days of an acute MI and/or percutaneous coronary angioplasty (caused by unstable angina) revealed clear cardiovascular benefits in 70 of the 126 total patients. A trend was observed at 6 months (P ⫽ .078), and a profound 72% reduction (odds ratio 0.28, 95% CI 0.13-0.6, P ⫽ .005) in cardiovascular end points at 2 years.8 The FLuvastatin On RIsk Diminishing After acute myocardial infarction (FLORIDA) trial20 (n ⫽ 540), although providing no overall cardiovascular influences from early statin therapy, revealed a beneficial trend after 1 year in patients with severe ischemia at baseline (P ⫽ .08). Funding issues terminated this study prematurely.

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A second line of support comes from the outcomes of large lipid-lowering analyses conducted after discharge. Data from the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Supression Using Integrelin Therapy (PURSUIT) and Global Use of Streptokinase or Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO IIB) trials were evaluated10 for 30-day and 6-month mortality in patients with ACS who were discharged while taking lipid-lowering therapy (n ⫽ 3653) compared with those patients not discharged who were taking similar medications (n ⫽ 17,156). Lipid-lowering therapy was associated with a clear benefit for all-cause mortality at 30 days (hazard ratio [HR] 0.44, 95% CI 0.27-0.73, P ⫽ .001) and 6 months (HR 0.48, 95% CI, 0.37-0.63, P ⬍ .0001) after discharge. Even after covariate and propensity score adjustments, the HR for mortality after 6 months continued to be significant (HR 0.67, P ⫽ .023). This experience parallels an analysis in which statin treatment given to a patient population in Sweden after MI was initiated before or at the time of hospital discharge.11 A total of 5528 patients received statin therapy, and 14,071 did not. After adjusting for confounders, early statin treatment in this cohort was associated with a 25% reduction (HR 0.75, 95% CI 0.63-0.89, P ⬍ .001) in mortality at the 1-year follow-up observation. Although no associated statistical comparisons were provided, the separation of the survival curves was clearly seen earlier than 1 year after the event. Retrospective analyses of the Maximal Individual Therapy in Acute Myocardial Infarction (MITRA 2, n ⫽ 2268),21 Platelet Receptor Inhibition for ischemic Syndrome Management (PRISM, n ⫽ 1616),22 Intravenous nPA Treatment of Infarcting Myocardium Early II (InTIMEII, n ⫽ 14,124),23 and Orbofiban in Patients with Unstable coronary Syndromes (OPUS-TIMI 16, n ⫽ 10,288)24 trials were reported to again reveal similar results. Recently reported data from the Sibrafiban versus Aspirin to Yield Maximum Protection from Ischemic Heart Events Post acute coronary syndromes (SYMPHONY) and second SYMPHONY (n ⫽ 15,904) trials, however, found no significant benefits of early initiation of statin therapy on hard clinical end points.25 Therefore, most current evidence supports the finding that in patients taking statin, and perhaps even in those initiated on statin therapy at the time of the acute episode, a cardiovascular advantage is appreciated within 3 to 4 months of an acute coronary event, an interval that is shorter than that typically observed in chronic studies (ie, Scandinavian Simvastatin Survival Study [4S],26 Cholesterol And Recurrent Events [CARE]27). It is not clear whether these benefits are associated with a lowering of LDL. However, statins are known to provide outcome benefits when initiated in subjects with a baseline LDL ⱖ125 mg/dL (CARE),27

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and recent unpublished data (Oxford trial, 2001) recommend therapy even to baseline LDL values ⬍100 mg/dL. Use of aspirin and ␤-blockers after MI and use of angiotensin-converting enzyme inhibitors are edging toward universal applications among patients with coronary artery disease.28 They are provided currently without previous data for platelet receptor genotypes29 or specific baseline blood pressure triggers.30 We predict that a cohort of patients after ACS provided with statin agents, as followed in the MIRACL study,7 would similarly result in overall benefit. The 1999 American Heart Association/American College of Cardiology guidelines for the management of patients with acute coronary syndromes31 suggest statin use if LDL is ⬎100 mg/dL. Despite these recommendations and the persuasive supporting evidence, including safety, investigators from the National Registry of Myocardial Infarction–3 recently reported only a 31.7% use of lipid-lowering medications in patients discharged after an MI.32 Mandated requirements to meet specific LDL-C serum concentrations before initiation of drug therapy6,31 add process-related impediments to the successful prescription and use of statin drugs. Because ⬎80% of patients after MI have baseline LDL-C ⬎100 mg/dL,33 and because statins in this setting may operate, at least temporarily, through nonLDL avenues, more routine use of these agents peridischarge without previous evaluation of LDL-C triggers should be considered. However, the universal institution of a “statin-for-all” policy has associated concerns. Some small-butsignificant percent of patients with ACS would be treated outside of current ATP III guidelines (eg, without adequate published evidence). However, the recently reported results of a randomized placebo-controlled simvastatin trial (n ⬎ 20,000),12 which revealed a 25% reduction in cardiovascular risk irrespective of baseline cholesterol levels (including LDL-C values ⬍100 mg/dL), assuage these concerns. The provision of therapy for these patients, although potentially beneficial, could result in other deleterious outcomes and/or unnecessarily expose patients to drug-related risk. In addition, the added cost to such an approach is unknown. In summary, the marked benefits that could be achieved with universal statin treatment after ACS must be countered by potentially less positive outcomes in a very small percentage of patients. Costbenefit analyses that would view statin therapy in this high-risk group as advantageous are speculative. Overall, we conclude that statin therapy should be initiated in the setting of ACS, regardless of plasma lipid values.

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