Periprocedural loading dose of Atorvastatin reduces MACE in patients with ACS undergoing PCI: Is this a Pleiotropic effect? Timing of Loading Dose of Atorvastatin in Patients Undergoing Percutaneous Coronary Intervention for Acute Coronary Syndromes: Insights From the SECURE-PCI Randomized Clinical Trial

A study by Lopes and his colleagues published in JAMA Cardiology has shown that in patients with ACS undergoing PCI, periprocedural loading doses of atorvastatin appeared to reduce the rate of Major Adverse Cardiovascular Events (MACE) at 30 days, primarily in patients with ST-segment elevation myocardial infarction. Insights from the Statins Evaluation in Coronary Procedures and Revascularization (SECURE-PCI) randomized clinical trial showcased this beneficial effect to be preserved and consistent, regardless of the timing of atorvastatin administration, including within 2 hours before PCI.

The SECURE-PCI trial showed that routine administration of two early doses of high-dose atorvastatin is not superior to placebo in reducing cardiovascular events at 30 days among patients presenting with ACS and scheduled to undergo an early invasive approach. It is a fact that increased use of statin therapy as part of the inhospital management of patients with ACS has occurred in parallel with the greater use of coronary angiography and early revascularization. This raises the question of whether very early administration of statin therapy, prior to any potential revascularization, may provide additional clinical benefit. Although early revascularization has been demonstrated to result in fewer adverse cardiovascular events in patients with ACS, percutaneous coronary intervention (PCI) has the potential to result in distal embolization of atheromatous material, which may result in ischemic complications. This may be more likely to happen in the setting of lipid-rich plaque and inflammatory plaque underlying acute ischemic events. Administration of statins prior to any potential PCI might be of benefit, which is supported by observations from mechanistic studies demonstrating that statin use prior to PCI has favorable effects on platelet reactivity, oxidative and inflammatory biomarkers, microvascular obstruction, and circulating markers of myonecrosis. Therefore, Lopes et al. raised the question if the timing of a loading dose of atorvastatin before percutaneous coronary intervention (PCI) affected 30-day major adverse cardiovascular events in patients presenting with acute coronary syndrome.

In this study, the investigators conducted a secondary analysis of a multicenter, double-blind, placebo-controlled, randomized clinical trial conducted at 53 sites that enrolled 4191 patients with ACS intended to be treated with PCI between April 18, 2012, and October 06, 2017.  Over a period of more than 5 years, the investigators randomized these 4191 patients with ACS to receive 2 loading doses of atorvastatin, 80 mg, or placebo before and 24 hours following a planned PCI procedure. All patients were subsequently treated with atorvastatin, 40 mg/d, for the remaining 30 days. The primary outcome was MACE through 30 days, which was a composite of all-cause mortality, myocardial infarction, stroke, and unplanned coronary revascularization. Cox regression models adjusting for key baseline characteristics were used to assess the association between atorvastatin and MACE in patients undergoing PCI.

Lopes et al. reported that even though many patients proceeded to PCI (64.7%) or coronary artery bypass graft surgery (8%), more than one-quarter of patients with ACS did not undergo coronary revascularization. Such findings provide important insights into the heterogeneity that is encountered with contemporary patients with ACS. The primary endpoint occurred in 6.2% of patients in the atorvastatin group vs 7.1% of patients in the placebo group, but this difference did not meet statistical significance (P = .27). As a result, the take-home message of the SECURE PCI study is that the routine use of loading doses of atorvastatin among ACS patients with intended invasive management cannot be supported. However, loading atorvastatin was associated with reduced MACE at 30 days by 28% in the PCI group (adjusted hazard ratio [HR], 0.72; 95% CI 0.54-0.97; P = .03). The reported rate of 30-day major adverse cardiovascular events was 6.0% among patients who received loading doses of atorvastatin and 8.2% among patients who received placebo. This effect was more pronounced in patients with ST-elevation myocardial infarction and consistent, irrespective of the timing of loading dose atorvastatin before PCI.

Loading doses of atorvastatin in patients with acute coronary syndrome undergoing PCI were not associated with any adverse effects and were associated with lower rates of major adverse cardiovascular events at 30 days, most clearly in patients with ST-elevation myocardial infarction. This benefit was maintained irrespective of the timing of administration of statin prior to PCI. Considering that LDL-C levels were similar in both arms (both arms received 40 mg of atorvastatin daily after the initial load), and the benefit in the PCI patients occurred early, the mechanism for benefit in these patients is likely due to the pleiotropic effects of statins. The study also highlights how heterogeneous an ACS population can be, both from a risk and a clinical response perspective.

Pondering the clinical implications of the study, Dr. Stephen J. Nicholls and Dr. Peter J. Psaltis write in an accompanying editorial, “Given that patients presenting with an ST-segment elevation myocardial infarction typically proceed directly to the catheterization laboratory when available, the findings from this study may present new challenges in terms of immediate statin administration in the emergency department. The demonstration of potential benefit would likely provide further support for the influence of nonlipid-lowering effects of atorvastatin, although this continues to require investigation. Although this prespecified subgroup finding involving patients who underwent PCI can be viewed only as hypothesis generating, it provides some ongoing enthusiasm that very early use of high-intensity statin therapy may be of benefit in the right patients.” They profess that while a generation of lipid-lowering studies has supported the concept “the lower and longer, the better” and, in ACS patients, “early is good,” it remains to be established whether this concept will evolve to “the earlier, the lower, and the longer, the better.” Only sufficiently large clinical trials may provide such answers.

To view the interview with Dr. C. Michael Gibson, click here.

To view the slides presented at TCT 2018, click here.