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Management of the acute coronary syndrome patient

D.D. Waters* and K.K. Khush

Department of Cardiology, Division of San Francisco General Hospital, San Francisco, CA, USA

* Correspondence: D.D. Waters, Department of Cardiology, Division of San Francisco General Hospital, Room 5G1, 1001 Potrero Avenue, San Francisco, CA 94110, USA. Tel.: +1-415-206-8320; fax: +1-415-206-5100
dwaters{at}medsfgh.ucsf.edu

Abstract

Clinical trials have shown that the lowering of total cholesterol or low-density lipoprotein cholesterol levels substantially reduces the risk of morbidity and mortality due to coronary heart disease. However, the benefits of lipid lowering in patients with acute coronary syndromes have been less well studied. The majority of statin trials excluded patients who had experienced recent unstable angina or acute myocardial infarction and, therefore, were not able to evaluate the potential beneficial effects that may result from early statin therapy. However, new evidence is emerging that statins may be effective immediately after an acute coronary event. Recent observational studies indicate that patients who are treated with a statin early after a coronary event have a more favourable outcome than those who are not, and retrospective analyses of clinical trial databases of patients with acute coronary syndromes have also shown this pattern. Statin therapy favourably impacts interrelated pathophysiologic mechanisms that are intimately involved in the pathogenesis of acute coronary syndromes, most notably endothelial function, platelet thrombus deposition and inflammation. The first clinical trial to study early statin intervention in acute coronary syndromes is the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study, which has demonstrated that lipid-lowering therapy initiated during hospitalization results in an early reduction in the incidence of recurrent ischaemic events.

Key Words: Acute coronary syndrome • Acute myocardial infarction • Lipid-lowering therapy • Statin • Unstable angina

Introduction

Three major trials have shown that treatment of stable coronary patients with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) reduces mortality and recurrent coronary events.1–3 In addition, in a population of Scottish men with hypercholesterolaemia,4 and in a population of Texans with average levels of low-density lipoprotein (LDL)-cholesterol and slightly low levels of high-density lipoprotein (HDL)-cholesterol5 (both of which populations were without previously documented coronary disease), treatment with a statin reduced the risk of a first coronary event. In the Heart Protection Study (HPS), which enrolled a broad spectrum of patients at risk for coronary events, major vascular events were reduced by approximately 25% in all categories of patient, including those with low baseline LDL-cholesterol levels.6

There appears to be a close relationship between LDL-cholesterol reduction and event reduction in both primary and secondary prevention trials across the range of LDL-cholesterol levels studied to date (from 200 mg/dl to less than 100 mg/dl). Event reduction does not appear to begin immediately, particularly in the secondary prevention trials. In the Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) trial, the Kaplan–Meier curves do not separate until approximately 1 year, as compared to 1.5 years in the Scandinavian Simvastatin Survival Study (4S), and 2 years in the Cholesterol And Recurrent Events (CARE) trial. This pattern may reflect the time course of plaque stabilization, the pathophysiologic mechanism to which the benefit of statins is usually attributed.

Early treatment with statins after an acute coronary event

Patients with a recent acute coronary syndrome were specifically excluded from the early statin trials. The interval from a prior infarction had to have been at least 6 months in 4S and at least 3 months in CARE and LIPID.1–3 Yet recent observational studies indicate that patients who are treated with a statin early after a coronary event have a much more favourable outcome than those who are not.7–9

A prospective cohort study using data from the Swedish Register of Cardiac Intensive Care (RIKS-HIA) showed that early initiation of statin treatment in patients with acute myocardial infarction was associated with a reduced 1-year mortality.7 The study compared 5528 patients who received statins at or before hospital discharge with 14,071 who did not. At 1 year, mortality was 4.0% in statin users and 9.3% in non-users. This difference narrowed considerably after adjustment for confounding factors, but early statin treatment was still associated with a reduction in 1-year mortality, with a relative risk of 0.75 (95% confidence intervals [CI] 0.63–0.89; ).

Retrospective analyses of clinical trial databases of patients with acute coronary syndromes have also shown this pattern. In the 20,809 patients who were discharged from hospital after an acute coronary syndrome in the Global Use of Strategies To Open Occluded Coronary Arteries in Acute Coronary Syndromes (GUSTO IIb) trial, and the Platelet glycoprotein IIb/IIIa in Unstable angina:Receptor Suppression Using Integrilin Trial (PURSUIT), those treated with a lipid-lowering drug exhibited a survival advantage that was already apparent at 1 month.8 The adjusted risk ratio for 6-month mortality was 0.67 (95% CI 0.48–0.95; ). Similarly, in a preliminary report from the Orbofiban in Patients with Unstable coronary Syndromes, Thrombolysis In Myocardial Infarction (OPUS-TIMI 16) trial, mortality at 1 month was reduced in patients treated with lipid-lowering drugs (94% of which were statins) compared with those who were not (0.7% versus 2.4% []).9

In each of these three observational studies, patients who were treated with lipid-lowering drugs were younger and healthier than patients who were not given this treatment. The apparent benefit from early statin therapy decreased in each population after adjustment for variables known to affect prognosis. Physicians are probably much less likely to prescribe statins after an acute coronary event in patients perceived to have a poor prognosis, and this selection bias may account for all, and not just a part, of the apparent benefit observed with statin use in these three reports.

Among 12,365 patients not taking statins at the time of an acute coronary syndrome and included in the SYMPHONY (Sibrafiban versus aspirin to Yield Maximum Protection from ischemic Heart events pOst-acute coroNary sYndromes) trials, 90-day and 1-year unadjusted mortality rates were lower in those started on a statin early after the event.10 However, this benefit disappeared after adjustment for differences between the groups. The disparity among the observational trials indicates that randomized trials of statin therapy started early after an acute coronary event are necessary to assess the value of this approach.

The process of plaque stabilization, defined as a decrease in the lipid pool and an increase in fibrosis of a vulnerable lesion, is unlikely to occur quickly enough to influence events in the early weeks following an episode of unstable angina or myocardial infarction. However, statins have recently been shown to exert a variety of beneficial effects, closely related to the pathophysiology of acute coronary syndromes. These effects include improvements in endothelial function, a decrease in the propensity for platelet thrombus formation, and a reduction in inflammation at the site of the lesion.11 Accumulating evidence suggests that these mechanisms may begin to be effective very early after the initiation of therapy, and that they are interrelated, so that a beneficial effect on one mechanism favourably influences the others.

For example, a decrease in nitric oxide (NO) resulting from endothelial dysfunction increases thrombogenicity through several pathways, and NO directly inhibits inflammation in coronary lesions.

Unstable versus stable coronary disease

A consideration of the potential beneficial actions of statins in patients with acute coronary syndromes could begin by emphasizing the distinction between acute and chronic coronary disease. Unstable coronary disease constitutes a unique syndrome with a distinct pathophysiology and prognosis, both of which differ from stable coronary disease. The difference in short-term prognosis can be appreciated by a comparison of patients with unstable angina or non-Q-wave myocardial infarction and patients with stable angina from the same geographic region. The Fragmin and fast Revascularization during InStability in CAD II (FRISC II) trial12 studied 2457 Scandinavian patients with acute coronary syndromes and found the rate of death, or nonfatal infarction with modern treatment, to be 13% during 1 year of follow-up. In contrast, the Swedish Angina Pectoris Aspirin Trial (SAPAT)13 studied 1026 stable angina patients treated with aspirin and a ß-blocker and found the rate of death and nonfatal infarction to be less than 2% in the first year of follow-up. This 6-fold difference in major events suggests that unstable and stable coronary disease represent very different processes.

The study by Chen et al.14 from St George's Hospital Medical School in London provides insight into the pathophysiology accounting for these prognostic differences. In this study, patients whose symptoms of unstable angina were controlled on medical therapy were put on a waiting list for coronary angioplasty if their culprit lesion met standard accepted criteria. During a mean waiting period of 8±4 months, 29 of the 95 unstable angina patients suffered a recurrent coronary event compared with only 25 in a comparison group of 200 stable angina patients (31% versus 13%; ).

Progression of the culprit lesion was documented to be the cause of the recurrent event in 15 of the 28 unstable angina patients with recurrent events who underwent repeat coronary arteriography. Culprit lesions were more often complex in unstable compared to stable patients. Lesions were categorized as complex if they had an irregular border, overhanging edges or thrombus. Complex lesions in unstable angina patients progressed more often during the 8-month follow-up interval compared with complex lesions in the stable angina patients (38% versus 19%; ). Stenosis severity was similar in the 2 groups (66%) and was not a predictor of progression. In fact, the only 2 predictors of progression in the whole population were unstable angina at initial presentation () and complex lesion morphology (). Thus, the incremental risk in unstable compared to stable angina can be partly attributed to the features of the unstable culprit lesion. However, patients with 1 unstable plaque are more likely than patients with stable coronary disease to already have, or to develop, other unstable plaques.15 The factors that precipitate plaque instability, inflammation and heightened macrophage activity are likely to be active at multiple sites in susceptible patients.

Remarkable therapeutic advances in the treatment of acute coronary syndromes have been made with antiplatelet and antithrombotic therapy, and it could be argued that future improvements in this area would be likely to produce only small increments in benefit. Nevertheless, antiplatelet and antithrombotic therapies alone do not appear to completely stabilize culprit lesions, because the risk of recurrent events after an episode of unstable angina or non-Q-wave infarction still remains several-fold higher than the risk level in stable coronary disease.

These considerations suggest that major advances in the treatment of these acute coronary syndromes are likely to come from completely different approaches. Evidence has been accumulating that intensive cholesterol lowering with statins favourably influences a multitude of interrelated processes relevant to the pathophysiology of recurrent events in acute coronary syndromes.

Cholesterol lowering and endothelial function

NO is released by a normally functioning endothelium in response to acetylcholine, which serves to dilate the artery. If the endothelium is dysfunctional, NO will not be released and the vessel will constrict as a result of the direct effect of acetylcholine on underlying smooth muscle. Thus, graded doses of intracoronary acetylcholine can be used to assess the endothelial function of coronary arteries. In addition, a good correlation has been demonstrated between coronary and brachial endothelial function.16 A non-invasive method has been developed to measure endothelial function that involves using B-mode ultrasound to measure arterial diameter before and after obstructing flow in the brachial artery using a blood pressure cuff.

Patients with hypercholesterolaemia,17 or multiple coronary risk factors,18 exhibit impairment of coronary endothelial function. Early studies of cholesterol lowering with lovastatin and pravastatin showed an improvement in coronary endothelial function, after 6 months or more of therapy.19–21 This time frame was presumably selected in these studies because damaged endothelium takes several weeks to regenerate in experimental animals. However, in more recent reports, cholesterol lowering has improved endothelial function more rapidly. In 1 study, treatment with simvastatin (20 mg/day) improved the brachial blood flow response to acetylcholine at 1 month with additional improvement at 3 months.22

Tamai et al.23 have reported that endothelial function can improve after a single 2-hour session of LDL apheresis (Fig. 1). LDL-cholesterol was lowered from 142 to 33 mg/dl, a far more rapid and profound decrease than can be attained with drugs. Forearm blood flow, measured by strain gauge plethysmography at incremental doses of acetylcholine, increased dramatically. This rapid improvement in endothelial function was accompanied by an increase in the local production of NO metabolites.



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  		Fig. 1 Acute effect of cholesterol lowering on endothelium-dependent vasodilation.23

 
Indeed, NO production and breakdown, and the biochemical pathways that regulate them, are the basic determinants of endothelial function. Statins have recently been shown to interact with these pathways at several points to favourably affect NO availability.24 LDL-cholesterol increases the vascular production of superoxide anion, which rapidly inactivates NO.25 Oxidized LDL-cholesterol interferes with the signal transduction pathways that link endothelial cell surface receptors with the actual production of NO.26 Statins, however, have been shown to decrease endothelial cell superoxide production not only through LDL-cholesterol reduction but also directly, by preventing the isoprenylation of p21 rac, a small G-protein involved in the assembly and function of the superoxide-forming NADPH oxidase.27 Statins also up-regulate the expression of endothelial NO synthase.28 This appears to be a consequence of the reduction in geranylgeranyl pyrophosphate (GGPP) induced by HMG CoA reductase inhibition. GGPP normally permits another small G-protein, rho, to attach to the cell membrane; rho activation signals the destabilization of endothelial NO synthase mRNA, resulting ultimately in less NO production. Statins thus prevent rho activation by reducing GGPP levels.29

Lastly, NO synthase activity is inhibited by caveolin-1, a scaffolding protein located in cell wall invaginations termed caveloae.24 Atorvastatin, in turn, inhibits caveolin-1 expression and through this mechanism also increases NO synthase activity.30 This effect of atorvastatin is probably mediated through LDL-cholesterol reduction, because it can be attenuated by the addition of LDL.30

Nearly all of the studies of endothelial dysfunction excluded patients with unstable coronary disease. Culprit lesions of patients with unstable angina have been shown to constrict in response to exercise or cold pressor stimulation, in contrast to the culprit lesions of patients with stable angina.31 It thus seems important to demonstrate that endothelial function can be improved by cholesterol lowering in patients with unstable, as well as stable, coronary disease.

The REduction of Cholesterol in Ischemia and Function of the Endothelium (RECIFE) Trial provides such evidence32 In this study, 60 patients with acute coronary syndromes were randomly assigned to either placebo or to pravastatin therapy during hospitalization. Endothelial function was measured via flow-mediated vasodilation in the brachial artery at baseline and after 6 weeks of therapy. Flow-mediated vasodilation improved in the statin-treated patients, but not in controls. Whether endothelial function also improved at the site of the culprit coronary lesion of such patients is unknown.

The endothelium plays a key role in the pathophysiology of acute coronary syndromes. The inadequate vasodilation due to endothelial dysfunction would be expected to facilitate turbulence and stasis around a severely stenotic culprit lesion, favouring further thrombosis. The balance between thrombosis formation and spontaneous thrombolysis appears to be crucial to the outcome of acute coronary syndromes. A lack of NO enhances thrombogenicity by several pathways, including increased platelet adhesion, inhibition of plasminogen activator and stimulation of plasminogen activator inhibitor, induction of the procoagulant tissue-factor messenger RNA, inhibition of messenger RNA transcription of thrombomodulin, and stereochemical alterations in heparin sulfate proteoglycans.33

The initiation of intensive cholesterol lowering with a potent statin might exert a favourable influence on NO production and breakdown at the site of the culprit lesion within days. The direct effects of NO, and its indirect beneficial effects upon thrombogenicity, might lead to a reduction in recurrent coronary events.

Cholesterol lowering and platelet function

The interaction between the platelet and the vessel wall at the site of plaque rupture determines whether or not an acute coronary syndrome will develop and how severe it will be. Hyperlipidaemia augments platelet aggregation and increases the production of thromboxane B2 by platelets in vitro.34–36 However, the relevance of these measurements to mural thrombus formation at the site of plaque rupture is uncertain. To simulate this situation experimentally, Badimon et al.37 developed a perfusion flow chamber containing a strip of porcine aortic media over which flowing venous blood could be drawn at different shear rates to measure platelet thrombus deposition. Applying this experimental model to patients with stable coronary disease, Lacoste et al. demonstrated that platelet thrombus deposition was more than twice as high in those with hypercholesterolaemia compared with those with lower cholesterol levels (Fig. 2).38 After 2.4 months of pravastatin treatment, the high blood cholesterol and increased platelet thrombus deposition returned to normal levels (Fig. 2). Mural thrombus deposition correlated with LDL-cholesterol levels (). This observation has been extended to women with hyperlipidaemia39 and to subjects with elevated cholesterol levels, but without known coronary disease.40



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  		Fig. 2 Cholesterol levels and platelet thrombus deposition.38 * normocholesterolaemic versus hypercholesterolaemic (basal) at both shear rates. {dagger} basal versus after pravastatin at both shear rates.

 
A mechanism explaining how hypercholesterolaemia increases platelet thrombus deposition has been defined.41 The Na+/H+ antiport located on the platelet membrane is inhibited by LDL-cholesterol, preventing it from counteracting the intracellular acidification that is associated with activation. By inhibiting the Na+/H+ exchange mechanism, LDL-cholesterol enhances platelet reactivity to activating stimuli. In patients with familial hypercholesterolaemia, lowering LDL-cholesterol with apheresis increased Na+/H+ antiport activity and intracellular pH. The observation that hypercholesterolaemia increases platelet thrombus deposition has important implications for the initiation of both initial and recurrent coronary events. In an autopsy study of middle-aged subjects dying from non-cardiac causes, such as accidents, Davies et al. found a coronary plaque rupture in 8.7% of cases.42 The incidence rose to 16.7% if diabetes or hypertension were present. Plaque rupture may therefore be a relatively common phenomenon, with only a small minority of ruptured plaques evolving to produce a clinical event. That hypercholesterolaemia doubles the rate of platelet thrombus deposition at the site of a plaque rupture would seem to be an important determinant of whether a clinical event occurs.

The interaction between platelets and the endothelium is extremely complex. Harmful or helpful effects on one system or the other are likely to be magnified by their interaction. The effects of cholesterol lowering on platelets and endothelium are likely to be synergistic, and to influence the outcomes of acute coronary syndromes.

Cholesterol lowering and inflammation

The pathophysiology of atherosclerosis involves inflammation, and inflammation appears to be a pivotal component of the process that transforms stable coronary disease to unstable coronary disease. Higher blood levels of inflammatory markers are associated with an increased risk of coronary events. C-reactive protein (CRP), a non-specific acute-phase inflammatory reactant, has been correlated with coronary risk more extensively than have other inflammatory markers, and can now be measured easily using a high-sensitivity assay. Among patients with stable43 or unstable44 angina, elevated CRP levels strongly predict future coronary events. CRP levels in the upper quintile, but still within the normal range, predict coronary events over the ensuing 5 years in both middle-aged men45 and women46 with no evidence of coronary disease.

The first report clearly documenting the effect of a statin on CRP levels involved a subgroup of patients who completed the CARE trial without adverse coronary events.47 Mean CRP levels increased over 5 years by 19.4% () in placebo-treated patients and decreased by 18.4% () in those assigned to pravastatin. Furthermore, the highest event rate in CARE occurred in placebo patients with CRP and serum amyloid A levels above the 90th percentile.48 The reduction in recurrent coronary events with pravastatin treatment was much greater in patients with these high levels of inflammatory markers compared with the rest of the study population.

Recent studies have clearly demonstrated that CRP levels can be reduced rapidly after the initiation of statin therapy, and that this reduction is a class effect of statins and not restricted to pravastatin alone. Eight weeks of treatment with cerivastatin 0.4 and 0.8 mg reduced LDL-cholesterol levels by 37% and 42%, respectively, in a study of 785 patients with primary hypercholesterolaemia, with corresponding reductions of 11% and 13% in CRP levels.49 All of these changes were statistically significant. In a double-blind crossover trial of 22 patients with combined hyperlipidaemia, the effects of equipotent doses of simvastatin (20 mg/day), pravastatin (40 mg/day) and atorvastatin (40 mg/day) on CRP levels were compared.50 All 3 statins significantly reduced CRP levels, from 2.6 mg/l at baseline to 1.7 mg/l with both atorvastatin and simvastatin, and 1.9 mg/l with pravastatin (Fig. 3).



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  		Fig. 3 Effect of statins on hs-C-reactive protein levels.50 (Double-blind, cross over trial of 22 patients with combined hyperlipidaemia. Six weeks of therapy with equipotent doses of pravastin (40 mg), simvastatin (20 mg) and atrovastatin (10 mg). Each statin significantly reduced hs-CRP levels.)

 
Statins attenuate the inflammatory manifestations of atherosclerosis through a variety of mechanisms. In a rabbit model of atherosclerosis, atorvastatin abolished macrophage infiltration, decreased monocyte chemoattractant protein levels in the neo-intima and in the media, and decreased activation of nuclear factor kappa-B in macrophages and vascular smooth muscle cells.51 Atorvastatin also reduces nuclear factor kappa-B levels and chemokine expression in cultured vascular smooth muscle cells and mononuclear cells.52

Whether CRP is just a marker of increased risk or a mediator of atherogenesis is an important distinction that may ultimately determine the clinical value of reducing CRP levels. In a recent study, CRP was shown to facilitate LDL-cholesterol uptake by macrophages, producing foam cells (Fig. 4).53 Foam cell formation can also result from macrophage uptake of oxidized LDL-cholesterol. That CRP can also mediate this key step in atherogenesis suggests that it is much more than just a marker.



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  		Fig. 4 Macrophages take up LDL incubated with C-reactive protein more avidly than LDL alone.53

 
The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) trial

As discussed above, intensive cholesterol lowering with statins favourably influences interrelated pathophysiologic mechanisms that are intimately involved in the pathogenesis of acute coronary syndromes: endothelial function (primarily NO production and inactivation), platelet thrombus deposition and inflammatory processes. The first large-scale clinical trial to examine whether these mechanisms translate into clinical event reduction in patients with acute coronary syndromes is the MIRACL study.54 Between May 1997 and September 1999, 3086 patients hospitalized with unstable angina or non-Q-wave myocardial infarction were randomized within 24–96 h of hospital admission to atorvastatin 80 mg/day or to placebo. Patients for whom coronary revascularization was planned and those with total cholesterol levels above 270 mg/dl were excluded. The study treatment period lasted for 16 weeks, at which time mean LDL-cholesterol was 135 mg/dl in the placebo group and 72 mg/dl in the atorvastatin group. The primary end-point was a composite of death, nonfatal myocardial infarction, resuscitated cardiac arrest or recurrent symptomatic myocardial ischaemia with new objective evidence requiring emergency rehospitalization.

A primary end-point occurred in 228 patients (14.8%) in the atorvastatin-treated group and 269 patients (17.4%) in the placebo group (relative risk 0.84; 95% CI 0.70–1.00; ) (Fig. 5). Although all of the components of the primary end-point were lower in the atorvastatin group, the only one that attained statistical significance by itself was the category of worsening symptomatic myocardial ischaemia with new objective evidence of myocardial ischaemia requiring emergency rehospitalization (6.2% versus 8.4%; relative risk 0.74; 95% CI 0.57–0.95). In addition, the occurrence of nonfatal stroke, a secondary end-point, was lower in the atorvastatin group than in the placebo group (22 versus 9; ).55 Cholesterol-lowering therapy with atorvastatin 80 mg/day thus reduced ischaemic events within 16 weeks of an acute coronary syndrome.



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  		Fig. 5 MIRACL: primary efficacy measure – time to first event. Permission granted by the American Medical Association.54 (*Death [any cause], nonfatal MI, resuscitated cardiac arrest, worsening angina with new objective evidence and urgent rehospitalization.)

 
Other large trials of statins in acute coronary syndromes

Three other clinical trials that are currently underway will expand our knowledge of the effects of statins early after an acute coronary syndrome. The A to Z Trial includes an initial phase where patients with unstable angina or non-ST-elevation myocardial infarction are all treated with tirofiban and randomized to enoxaparin or unfractionated heparin.56 Stabilized patients, including patients with ST-elevation myocardial infarction not included in the original randomization, are then randomized to either simvastatin 40 mg/day or placebo. After 1 month, the dose of simvastatin is increased to 80 mg/day and, after 4 months, patients in the placebo arm begin taking simvastatin 20 mg/day. The projected enrollment for the second phase of the trial is 4500 patients. Follow-up will continue until 970 end-point events, defined as cardiac death, myocardial infarction or readmission for an acute coronary syndrome, have occurred.

The PRavastatin Or atorVastatin Evaluation and Infection Therapy (PROVE IT) Trial will randomize 4000 patients up to 10 days after an acute coronary syndrome to either pravastatin 40 mg/day or atorvastatin 80 mg/day, with a mean follow-up of 2 years.32 Patients with total cholesterol levels of 240 mg/dl or greater will be excluded. Patients are also randomized to the antibiotic gatifloxacin or to placebo, to determine whether antibiotic therapy reduces recurrent coronary events.

Conclusion

The 4S, CARE and LIPID trials have proven that patients with established coronary disease derive considerable long-term benefit from statin therapy. The MIRACL Trial indicates that early initiation of atorvastatin after an episode of unstable angina or non-Q-wave infarction reduces events over the ensuing 16 weeks. A growing number of studies provide mechanistic explanations for early benefit of cholesterol lowering with statins, and observational studies suggest that such treatment is beneficial.

Yet cholesterol-lowering therapy continues to be under-utilized in patients with acute coronary syndromes. In a survey of 138,001 patients, who were discharged from 1470 hospitals in the United States between 1998 and 1999 after having suffered a myocardial infarction, only 31.7% were prescribed a cholesterol-lowering drug.57 Hopefully, clinical trials of statins in acute coronary syndromes will lead to an increase in the proportion of coronary patients who will receive this beneficial therapy.

Addendum

The PRavastatin Or atorVastatin Evaluation and Infection Therapy (PROVE-IT) trial was published after this manuscript was written.58 In PROVE-IT, 4162 patients who had been hospitalized within the preceeding 10 days for an acute coronary syndromes were randomized to pravastatin 40 mg or atorvastatin 80 mg/day. The study was designed to establish the non-inferiority of pravastatin. Average follow-up was 24 months. The median LDL-cholesterol during treatment was 95 mg/dL in the pravastatin group and 62 mg/dL in the atorvastatin group. The rate of the primary end-point, a composite of all-cause mortality, myocardial infarction, documented unstable angina requiring hospitalization, and coronary revascularization, was 26.3% in the pravastatin and 22.4% in the atorvastatin group (). These findings demonstrate that among patients with a recent acute coronary syndrome, intensive cholesterol lowering to levels well below current targets provides greater protection against death or major coronary events than does standard therapy.

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