SECURE PCI: how important can a subgroup analysis be?

Among acute coronary syndrome (ACS) and stable coronary artery disease patients, the effect of a loading dose of statin, prior to revascularization, has been assessed in several observational studies and randomized controlled trials (1-3). A high dose of statin before percutaneous or surgical revascularization was associated with a decreased risk of periprocedural myocardial infarction (MI), contrast induced—acute kidney injury and, finally, improved clinical outcomes (4,5). The underlying mechanism was hypothesized to be related to the complex pleiotropic effects of statins which improve endothelial function, stabilize the atherosclerotic plaque, and decrease the vascular inflammation (6).

European and American Guidelines recommend the administration of statins in all patients with acute MI, irrespective of cholesterol concentration at presentation. In addition, lipid-lowering treatment should be started as early as possible (class I in European Guidelines, IIa in American Guidelines) and given as a high-intensity treatment (class I in both guidelines) (7,8). However, the efficacy of a high dose of statin, as a pretreatment, was evaluated in trials with small sample size and soft endpoints (9).

The SECURE-PCI study was an ambitious, multicenter, randomized controlled trial designed to address the limitations of previous studies. The trial had a large sample size (N=4,191), and strong methodology (10). Nevertheless, Berwanger et al. failed to demonstrate that two separate loading doses of 80 mg of atorvastatin administered among ACS patients was superior in the reduction of major adverse cardiovascular events (MACE) compared to placebo at 30 days (11). Since P of the primary endpoint comparison are too often translated into a ‘positive’ or ‘negative’ result (12), the SECURE PCI Trial was mainly reported as a ‘negative’ trial.

It might be unfair, however, to dismiss the SECURE PCI trial based on its primary endpoint alone analysis alone for three main reasons: (I) a prespecified and powered analysis among patients who underwent PCI demonstrated a 2.2% absolute reduction in the occurrence of the composite ischemic endpoint (P for interaction =0.04) mainly driven by a decreased rate of periprocedural MI and unplanned coronary revascularization, (II) the prior data and the rationale for the efficacy early high dose statin among patients undergoing revascularization is robust, (III) this strategy did not increase the occurrence of serious adverse events.

Indeed, the subgroup of patients who underwent PCI was a pre-specified sensitivity analyses in the protocol (10). Further, the sample size calculation for the trial was performed to maintain approximately 80% power for this analysis, though it should be noted the observed overall event rate was nearly half the estimated rate. Still, a significant result was observed (P=0.02, NNT =46) and a significant interaction was observed (P=0.04), indicating PCI status modulated the treatment effect of the loading dose of statin.

In daily practice, the vast majority of the ACS patients are already treated with a high dose of statin administered within the first 24 hours. This ‘routine care’ will likely not be influenced by the primary endpoint analysis of the SECURE PCI trial. More than 12 randomized studies, previously demonstrated the consistent benefit of a pretreatment with statin among patients undergoing PCI (9). Instead of only considering the scientific result of the primary endpoint analysis in one trial, physicians often take into account the pathophysiology, previous results, and the balance of benefit/risk to guide their decisions.

Of importance in the SECURE-PCI trial, no cases of rhabdomyolysis or hepatic failure were reported in the atorvastatin group. The safety of an early treatment strategy which will inevitably be given to the patient chronically counterbalances the lack adjustments for multiple testing or sequential order for the secondary analyses that may limit our conclusion (if a simple Bonferroni correction was applied to the subgroup analysis, the significance of the P would be lower)

While such an approach is safe, and the totality of the data suggests it is effective, it should not delay therapy in ACS patients, particularly STEMI patients. It is obvious, in particular, that the lack of administration of a loading dose of statin should never delay a transfer to the Cath lab or the administration of an antithrombotic regimen. However, in the Cath lab for STEMI patients, or in the coronary care unit for non-ST elevated ACS patients, giving a loading dose of statin seems easy, economic, harmless and may reduce the ischemic risk.

Acknowledgements

None.

Footnote

Conflicts of Interest: M Kerneis has received research grant support from French federation of Cardiology, Institut Servier, consulting fees or honorarium from Bayer and AstraZeneca. CM Gibson has received research grant support from Angel Medical Corporation, Bayer Corp, CSL Behring, Janssen Pharmaceuticals, Johnson & Johnson Corporation, and Portola Pharmaceuticals; and has received modest consulting monies from Amarin Pharma, Amgen, Arena Pharmaceuticals, Bayer Corporation, Boehringer Ingelheim, Boston Clinical Research Institute, Cardiovascular Research Foundation, Chiesi, CSL Behring, Eli Lilly, Gilead Sciences, Inc., Janssen Pharmaceuticals, Johnson & Johnson Corporation, The Medicines Company, Merk & Co, Inc., Novo Nordisk, Pfizer, Pharma Mar, Portola Pharmaceuticals, Sanofi, Somahlution, St. Francis Hospital, Verson Corporation, and Web MD. Another author has no conflicts of interest to declare.

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