Previous randomized studies have shown that pretreatment with statins improves clinical outcome in subjects with stable angina undergoing elective percutaneous coronary intervention (PCI)¹; in particular, the first Atorvastatin for Reduction of Myocardial Damage During Angioplasty (ARMYDA) trial showed that 7-day pretreatment with atorvastatin (Lipitor; 40 mg/day) was associated with an 81% risk reduction in the occurrence of periprocedural myocardial infarction (MI) and a significant postprocedural reduction in all markers of myocardial injury.¹ However, data on the effects of statins in subjects with acute coronary syndrome (ACS) treated with PCI are more limited.

Observational reports in the setting of acute MI have indicated that early initiation of statin therapy is associated with a decrease in in-hospital complication rates and reduction in infarct size²; in particular, analysis of data from a large registry including more than 20 000 subjects showed that administration of statins before discharge may translate into a 25% reduction in mortality.² Nonrandomized data on the early use of statins in subjects with non-ST-segment elevation acute coronary syndrome have yielded conflicting results: a decreased incidence of cardiovascular events during follow-up has been reported,³ whereas a post-hoc analysis of 12 365 subjects did not show a reduction in death, MI, and recurrent ischemia at 90 days in subjects receiving statins (odds ratio = 1.15).⁴ However, those subjects were treated with different types of statins, at different doses, and with an often unknown duration of therapy. The randomized Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) trial has shown that atorvastatin 80 mg given within 24 to 96 hours after admission for an unstable syndrome produced a modest but statistically significant reduction in the 4-month incidence of cardiovascular events (16% risk reduction), primarily driven by a 26% decrease in the recurrence of myocardial ischemia requiring hospitalization.⁵ Indeed, a recent meta-analysis including 13 024 subjects from 12 randomized trials comparing early (within 14 days) statin therapy with placebo or usual care after acute coronary syndrome has demonstrated no reduction in the incidence of death, MI, or stroke at 1 and 4 months in subjects receiving statins, and a 20% decrease in unstable angina that was not statistically significant.⁶ However, all these studies have mostly included subjects treated with a conservative strategy without early coronary intervention.

Various trials have also compared the efficacy of intensive versus moderate statin therapy in subjects with acute coronary syndrome. In the Aggrastat to Zocor (A to Z) study,⁷ early initiation of an aggressive simvastatin (Zocor) regimen (40 mg/day for 1 month followed by 80 mg/day thereafter) resulted in a statistically significant 25% risk reduction of cardiovascular events during 4 months to 2 years of follow-up compared with a less-intense simvastatin strategy (placebo for 4 months followed by 20 mg/day of simvastatin thereafter). Moreover, the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction (PROVE IT-TIMI) 22 trial compared atorvastatin therapy (80 mg) with pravastatin (Pravachol) therapy (40 mg) started in the first 10 days after admission; this study showed that atorvastatin was associated with a statistically significant reduction in cardiovascular events in the first 30 days after randomization (odds ratio = 0.72), mainly driven by a reduction in the recurrence of clinical instability, and the benefit was maintained over a 30-month period (odds ratio = 0.76).⁸ A recent meta-analysis including 27 548 subjects showed that intensive lipid lowering with high-dose statin therapy provided a significant benefit (odds ratio = 0.84) over standard-dose therapy for preventing predominantly nonfatal cardiovascular events.⁹ However, no randomized study has specifically assessed the effects of acute statin treatment in the setting of an early interventional strategy.

Observational evidence has indicated that subjects with acute coronary syndrome who were taking statins at the time of PCI had a lower incidence of periprocedural myonecrosis and better cardiac-event-free survival at 6 months.¹⁰ This issue was recently evaluated in the ARMYDAACS trial, which explored the possible beneficial clinical effect of an acute loading dose with high-dose atorvastatin in subjects with acute coronary syndrome undergoing early PCI.

Subjects and methods

The ARMYDA-ACS study, which was a multicenter, randomized, prospective, double-blind clinical trial, included 171 subjects with non-STsegment elevation acute coronary syndrome (unstable angina or non-STsegment elevation acute MI) who received coronary angiography within 48 hours.¹¹ Subjects were randomly assigned to receive placebo (n = 85) or atorvastatin (n = 86; an 80-mg loading dose was given about 12 hours before PCI, with a 40-mg dose given approximately 2 hours prior to the procedure). A 600-mg loading dose of clopidogrel (Plavix) was given to the entire study population, and glycoprotein IIb/IIIa inhibitors were used at the physicians' discretion. After the intervention, all subjects received atorvastatin (40 mg/day), regardless of randomization assignment. C-reactive protein (CRP), troponin I (mass), myoglobin, and creatine kinase-MB (mass) levels were assessed in all subjects before the intervention and at 8 and 24 hours after the intervention. The primary end point was the 30-day incidence of major adverse cardiac events (MACE; death, MI, or target vessel revascularization). The secondary end points were any postprocedural increase in myocardial injury markers and postprocedural changes from baseline CRP levels.

Figure 1. Individual and combined outcome measures of the primary end point at 30 days in the ARMYDA-ACS trial. MACE indicates major adverse cardiac events; MI,myocardial infarction;TVR, target vessel revascularization.

Results

A high proportion of subjects enrolled in the ARMYDA-ACS trial had clinical/angiographic features of a high-risk profile; about one third had diabetes or non-ST-segment elevation MI, about one fourth underwent multivessel PCI or received glycoprotein IIb/IIIa inhibitors, and 84% had B2/C target coronary lesions. Figure 1 shows the outcome measures of the primary end point. Subjects receiving atorvastatin had a significantly lower occurrence of the composite primary end point compared with those receiving placebo (5% vs 17%; P = .01), and the benefit was essentially the result of a reduction in periprocedural MI (5% vs 15%; P = .04). The benefit of statin pretreatment was independent of cholesterol levels, and it was expressed as an 88% risk reduction of 30-day MACE at multivariable analysis (Figure 2) and as a 70% reduction in the occurrence of periprocedural MI. According to these data, 10 subjects should be treated with atorvastatin to avoid 1 case of MI. With regard to the secondary end point, the prevalence of subjects with postprocedural elevation of creatine kinase-MB and troponin I was markedly reduced in the atorvastatin group (creatine kinase-MB, 7% vs 27%, P = .001; troponin I, 41% vs 58%, P = .039).

Figure 2. Multivariable analysis showing independent predictors of major adverse cardiac events (MACE) at 30 days in the ARMYDA-ACS trial. LVEF indicates left ventricular ejection fraction; CIs, confidence intervals.

Discussion

Mechanisms underlying the early clinical benefit of atorvastatin observed in the ARMYDA-ACS study are unclear, but they are not likely to be a result of cholesterol-lowering effects, which require a longer duration of treatment. Statins can also modify plaque components (with a reduction of lipids and macrophages and an increase of collagen), leading to plaque stabilization, although these effects have been shown with a treatment period of 1 to 4 months.¹² Several experimental studies have shown that a loading dose of high-dose statins may have relevant acute pleiotropic effects: (a) a single dose of 40 mg pravastatin has been associated with attenuation of acetylcholine-induced coronary vasoconstriction in subjects with coronary artery disease undergoing invasive evaluation of coronary endothelial function¹³; (b) an increase in the coronary flow velocity reserve has been shown on transthoracic Doppler evaluation of the left anterior descending artery at baseline and after 1 hour in subjects receiving a single dose of 40 mg atorvastatin¹⁴; (c) short-term administration of atorvastatin may have antithrombotic effects by reducing platelet CD40L expression, as well as production of prothrombin fragment F1+2¹⁵; (d) a prospective subanalysis of subjects in the first ARMYDA trial has shown a significant attenuation of post-PCI increase in adhesion molecule levels in the atorvastatin arm¹⁶; (e) acute administration of atorvastatin may reduce infarct size in a mouse model of ischemia-reperfusion, and this effect is related to direct myocardial protection mediated by mechanisms also involved in the ischemic preconditioning (rapid activation of phosphatidyl inositol 3-kinase and serine/threonine kinase and enhancement of AKT activity)¹⁷; and (f) various studies have indicated that inflammatory status correlates with prognosis in subjects with unstable coronary syndrome,¹⁸ and in such subjects, atorvastatin may significantly decrease levels of CRP during the acute phase and enhance the decline in inflammation during follow-up.¹⁹ In the ARMYDA-ACS study, atorvastatin has mostly reduced a postprocedural increase in CRP in subjects with higher baseline levels of this marker, suggesting that the anti-inflammatory effects of atorvastatin may be stronger in subjects with enhanced baseline inflammatory status. Thus, according to all these data, the clinical benefit observed in the ARMYDA-ACS trial may be the result of improvement of microvessel coronary function; limitation of procedural microembolization and microvessel clotting activation; attenuation of endothelial activation and proinflammatory mechanisms; and/or direct myocardial protection from procedural myocardial ischemia.

Conclusions

Findings of the ARMYDA-ACS trial support the indication for upstream administration of high-dose statins in subjects with ACS undergoing an early invasive strategy. Unresolved issues include the possible short-term benefits of high-dose statins in clinical settings that were not included in the ARMYDA-ACS trial among subjects with STsegment elevation acute MI, as well as in those with non-ST-segment elevation ACS requiring emergency invasive strategy, being treated medically, or receiving surgical revascularization.

References