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March 11, 2018

Lipid Lowering in Acute Coronary SyndromeIs Treatment Early Enough?

Author Affiliations
  • 1South Australian Health and Medical Research Institute, University of Adelaide, Adelaide, South Australia, Australia
JAMA. Published online March 11, 2018. doi:10.1001/jama.2018.2426

The beneficial effect of lipid lowering with statins in randomized clinical trials has had a profound effect on patient outcomes and informing treatment algorithms for cardiovascular prevention. These studies have increasingly emphasized the importance of the direct relationship between the degree of lipid lowering and clinical benefit, with the greatest effect observed among patients at the highest risk of having a subsequent cardiovascular event.1 Such observations have informed treatment guidelines, which strongly advocate for use of intensive statin therapy for patients with the highest cardiovascular risk.2

The data supporting early use of intensive statin therapy among patients with acute coronary syndrome (ACS) represented an important change in clinical practice. In the Myocardial Ischemia Reduction With Aggressive Cholesterol Lowering (MIRACL) study, administration of atorvastatin, 80 mg/d, within 24 to 96 hours of hospital admission among 3086 patients with ACS reduced the incidence of cardiovascular events (from 17.4% to 14.8%) during the subsequent 16 weeks in patients presenting with ACS.3 The Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) study subsequently demonstrated that among 4162 patients with ACS, administration of intensive lipid-lowering therapy with atorvastatin, 80 mg, was more effective than pravastatin, 40 mg, with a 16% reduction (from 26.3% to 22.4%) in cardiovascular events at 24-month follow-up, with benefit evident as early as 30 days.4 These findings had an immediate influence on clinical practice, with prescription of high-intensity statin therapy becoming common practice in the coronary care unit. The benefit of more intensive lipid-lowering regimens was more recently supported by observation of cardiovascular benefit via addition of the cholesterol absorption inhibitor ezetimibe, to simvastatin in 18 144 patients with ACS in the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT), albeit after a median follow-up of 6 years.5

These studies made a number of contributions to the management of patients with ACS. Most importantly, they supported the early use of high-intensity statin therapy. However, 2 of these studies (PROVE-IT and IMPROVE-IT) permitted initiation of therapy up to 10 days following the index ACS event. Given the diminishing length of hospital stay for most patients with ACS in contemporary practice, this suggests that many patients may not have received such therapy in hospital. This has not proven to be the case in clinical practice, in which statin prescription on discharge has become a key performance measure for ACS management. The early clinical benefit with high-dose atorvastatin in MIRACL and PROVE-IT also suggested potential non–lipid-lowering effects of statin therapy. This was supported by observations of an association between C-reactive protein lowering and favorable effects on both cardiovascular events6 and progression of coronary atherosclerosis7 with statin therapy.

Increasing use of statin therapy as part of in-hospital management of patients with ACS has occurred in parallel with 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,8 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.9 Although small studies have investigated potential effects of statins prior to PCI in patients with ACS,10 the effect on clinical outcomes in a sufficiently large study has not been investigated.

In this issue of JAMA, Berwanger and colleagues report the findings of the Statins Evaluation in Coronary Procedures and Revascularization (SECURE-PCI) trial, in which they aimed to determine if periprocedural administration of a loading dose of atorvastatin reduced the incidence of major adverse cardiovascular events at 30 days in patients with ACS undergoing clinically indicated coronary angiography.11 Over a period of more than 5 years, the investigators randomized 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. Two important observations were made during this study. First, 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. This likely reflects a combination of patients with no obstructive disease requiring intervention and those with widespread, diffuse disease for which revascularization would not provide a clinically useful option. Such findings provide important insights into the heterogeneity that is encountered with contemporary patients with ACS.

The primary end point, a composite of all-cause mortality, myocardial infarction, stroke, and unplanned coronary revascularization at 30 days, 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. To what degree this reflects sample size, based on an ambitious assumed event rate reduction, remains uncertain.

However, among patients who did undergo PCI, fewer events were experienced during the next 30 days among patients who received the atorvastatin loading doses compared with those who received placebo (6.0% vs 8.2%; P = .02). The difference in signal between this subgroup and the entire study cohort is likely related to the much higher event rate among patients in the placebo group who underwent PCI compared with those who did not (8.2% vs 5.0%), suggesting that these patients were higher risk.

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 non–lipid-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.

Are there clinical implications of these findings for the management of patients with ACS? Treatment guidelines already suggest that such patients should receive high-intensity statin therapy and that routine in-hospital initiation is likely to be of benefit for both prevention of subsequent cardiovascular events and increased long-term adherence to statin therapy, which is a cornerstone of secondary prevention. Whether such therapy should be administered as soon as possible in the ACS hospitalization remains to be fully elucidated. SECURE-PCI certainly provides reassurance that such early administration is not associated with harm. The subgroup findings suggest potential benefit among patients who are deemed more likely to undergo PCI at the time of angiography. To what degree such findings may be exclusive to intensive statin therapy, or whether similar results would be observed with early initiation of additional lipid-lowering agents, some of which do not appear to have pleiotropic effects in humans, is unknown. 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.

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Article Information

Corresponding Author: Stephen J. Nicholls, MBBS, PhD, South Australian Health and Medical Research Institute, PO Box 11060, Adelaide, South Australia, Australia 5001 (stephen.nicholls@sahmri.com).

Published Online: March 11, 2018. doi:10.1001/jama.2018.2426

Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Nicholls reports that he is supported by a Principal Research Fellowship from the National Health and Medical Research Council of Australia. He also reports receiving research support from AstraZeneca, Amgen, Anthera, Eli Lilly, Esperion, Novartis, Cerenis, the Medicines Company, Resverlogix, InfraReDx, Roche, Sanofi-Regeneron, and Liposcience and consultant fees from AstraZeneca, Amgen, Eli Lilly, Anthera, Merck, Takeda, Resverlogix, Sanofi-Regeneron, Kowa, CSL Behring, Esperion, and Boehringer Ingelheim. Dr Psaltis reports that he is supported by a Future Leader Fellowship from the National Heart Foundation of Australia. He also reports receiving research support from Abbott Vascular and honoraria from AstraZeneca, Merck, Pfizer, Esperion, and Bayer.

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