Statin use to reduce the incidence of PCI-associated periprocedural MI

Statins have been a mainstay of cholesterol-lowering therapy for decades. Whereas LDL reduction results from the inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase, additional beneficial properties of statins have been elucidated in recent studies.

These additional properties, also referred to as pleiotropic effects, appear to be independent of the lipid-lowering effect. The pleiotropic effects of statins include decreased inflammation and increased plaque stability, along with an improvement in endothelial function attributed to increased nitric oxide at the vasculature.

Michael Sim

Until recently, these pleiotropic effects have been observed primarily in animal models, whereas the clinical significance in real-world practice has been largely eclipsed by the well-established importance of chronic lipid-lowering. However, recent evidence suggests that statins are beneficial in acute CV settings such as percutaneous coronary intervention.

PCIs are invasive procedures that often result in adverse CV events, including increased inflammation, platelet adhesion and plaque instability during the procedure, which may result in elevations in cardiac enzymes or periprocedural MI. Periprocedural MI has been increasingly linked to worse CV outcomes, and cardiac enzymes such as creatine kinase-myocardial isoenzyme (CK-MB) are beginning to be used as markers of quality performance.

ARMYDA and NAPLES II studies

Several recent human studies have confirmed evidence from animal models documenting the beneficial effects of statins in the acute setting. An observational study found that patients pretreated with various statins for at least 1 week before PCI had a reduced incidence of periprocedural MI, defined as CK-MB greater than three times the upper limit of normal. Another study found a decrease in all-cause mortality, after 30 and 180 days, in patients on statin regimens during the time of PCI.

In 2004, the first randomized, controlled, double blind study — Atorvastatin for Reduction of Myocardial Damage during Angioplasty (ARMYDA) — was published, which aimed to determine whether atorvastatin 40 mg daily in statin-naive patients with stable angina, beginning 7 days before elective PCI, could reduce periprocedural MI (defined as CK-MB greater than two times the upper limit of normal). ARMYDA found a lower composite endpoint of death, MI and revascularization in the statin group, although it was due entirely to a lower incidence of periprocedural MI between the two groups (5% vs. 18%; P=.025).

The ARMYDA study required statin-naive patients to take atorvastatin (Lipitor, Pfizer) for 7 days, but the Novel Approaches for Preventing or Limiting Events II (NAPLES II) trial found a reduction in periprocedural MI after a single dose of atorvastatin 80 mg, up to 24 hours before PCI. NAPLES II was an open-label, randomized trial that primarily enrolled patients with stable angina undergoing elective stenting procedures. Patients were randomly assigned to receive atorvastatin 80 mg or no statin treatment on the day before PCI. The investigators found that the incidence of periprocedural MI (CK-MB elevation greater than three times the upper limit of normal) in the atorvastatin group was 9.5% vs. 15.8% in the control group (OR=0.56; 95% CI, 0.35-0.89). Interestingly, subgroup analysis suggested that patients with increased CRP at baseline were the greatest benefactors of the single high-loading dose of atorvastatin, supporting the notion that the benefits of statins are even greater in patients with underlying inflammatory processes.

Similarly, compared with no statin, a single 40-mg loading dose of rosuvastatin (Crestor, AstraZeneca) in statin-naive patients administered before PCI was associated with a lower incidence of periprocedural MI (CK-MB greater than two times the upper limit of normal; 11.4% vs. 5.8%, P=.035). All patients were then treated with 10 mg rosuvastatin daily post-PCI and followed for 12 months to assess CV outcomes. Patients who received the 40-mg loading dose pre-PCI had significantly lower incidence of major adverse CV events compared with the control group (9.8% vs. 20.5%, P=.002). Those in the control group had a threefold increased risk for death and non-fatal MI during follow-up (P=.02).

ARMYDA-ACS and ARMYDA-RECAPTURE

The ARMYDA-ACS trial aimed to evaluate the effects of a loading dose of atorvastatin in statin-naive patients with non-ST segment elevation acute coronary syndrome. The randomized, placebo-controlled trial investigated whether an 80-mg loading dose of atorvastatin 12 hours before angiography, along with an additional 40-mg dose 2 hours before PCI, would reduce 30-day incidence of major adverse CV events. ARMYDA-ACS found that the 30-day incidence of major adverse CV events occurred in 5% of the statin group vs. 16.5% in the control group (P=.01). However, this difference was almost entirely driven by a reduction in periprocedural MI (CK-MB greater than two times the upper limit of normal).

ARMYDA, NAPLES II and ARMYDA-ACS all demonstrated reduction in periprocedural MI in statin-naive patients, but most patients who require PCI in a real-world setting are already taking statins. This is further complicated by previous studies showing that statins lose their protective anti-inflammatory effects after as little as 1 or 2 weeks of use in animal models. However, the loss of protection due to long-term statin therapy may be overcome by an acute loading dose.

The ARMYDA investigators again studied whether an 80-mg loading dose of atorvastatin 12 hours before angiography along with an additional 40-mg dose 2 hours before PCI would lower 30-day incidence of major adverse CV events but, this time, in patients with stable angina and ACS who were receiving chronic statin therapy for at least 30 days before enrollment in the study. ARMYDA-RECAPTURE, published in 2009, found a significant decrease in 30-day major adverse CV events in those randomly assigned to the loading and additional dose (3.7% vs. 9.4%; P=.037). Again, this result was fueled mostly by a reduction in periprocedural MI (CK-MB greater than three times the upper limit of normal). Subgroup analysis showed a remarkable benefit for statin loading in the ACS group (OR=0.18; 95% CI, 0.10-0.83; RR=82%), whereas benefit in those with stable angina was not statistically significant (OR=0.74; 95% CI, 0.20-2.9).

These studies supplement a growing body of evidence for statin use beyond the traditional cholesterol-lowering indication. Although the studies have limitations, such as non-standardized statin dosing and varied definition of CK-MB to determine clinically relevant MI, results from these trials are changing the way clinicians view the role of statins.

Michael Sim, PharmD, is a clinical staff pharmacist at Arnold Palmer Children’s Hospital in Orlando, Fla.

Rhonda M. Cooper-DeHoff, PharmD, MS, is associate professor, Department of Pharmacotherapy and Translational Research, College of Pharmacy, and Division of CV Medicine, College of Medicine, University of Florida, Gainesville. Dr. Cooper-DeHoff is Cardiology Today’s Pharmacology Consult column editor and a member of the CHD and Prevention section of the Cardiology Today Editorial Board.

Disclosure: Dr. Sim reports no relevant financial disclosures.

For more information:

• Briguori C. J Am Coll Cardiol. 2009;54:2157-2163.
• Di Sciascio G. J Am Coll Cardiol. 2009;54:558-565.
• Pasceri V. Circulation. 2004;110:674-678.
• Patti G. J Am Coll Cardiol. 2007;49:1272-1278.
• Yun K. Int J Cardiol. 2009;137:246-251.
• Yun K. Int J Cardiol. 2011;146:68-72.