Benefit of ezetimibe/simvastatin for acute coronary syndrome questionable

New findings suggest that the trial population of IMPROVE-IT were younger, healthier and received more optimal secondary prevention therapies than current qualifying patients, challenging the use of ezetimibe/simvastatin in patients with acute coronary syndrome, according to a research letter published in JAMA Internal Medicine.

Perspective from

“The recent IMPROVE-IT trial demonstrated that adding ezetimibe to simvastatin in patients with recent acute coronary syndrome (ACS) reduced cardiac events by 2% over 7 years, but it is unclear to what degree these results impact clinical care,” Thomas M. Maddox, MD, MSc, from the University of Colorado School of Medicine, and colleagues wrote.

Maddox and colleagues used the American College of Cardiology practice innovation and clinical excellence (PINNACLE) ambulatory cardiology practice registry to identify current patients with ACE who would have qualified for IMPROVE-IT. They compared data from these patients with patients who participated in the trial.

The researchers identified 28,454 recent patients with ACS at 182 practices recorded within the PINNACLE registry between January 2013 and September 2014. Among those, 35.9% (n = 10,228) met the criteria for IMPROVE-IT enrollment, with practices showing modest variation (median, 34.5%; IQR, 25.6-42.9). Demographic, medical comorbidities and medication comparisons indicated that PINNACLE patients were significantly older and more likely to be female than IMPROVE-IT patients. In addition, PINNACLE patients had distinctly higher rates of peripheral arterial disease, heart failure and hypertension and lower rates of secondary prevention medication use.

These findings suggest that “it is unclear if the effect seen with simvastatin/ezetimibe use in the trial translates to current patients with ACS,” Maddox and colleagues concluded.

“One factor reducing the applicability of IMPROVE-IT to practice is its use of a moderate-intensity statin, which deviates from the current guideline recommendation to use high-intensity statins in all eligible patients with ACS,” they added. “In fact, as adherence to current guidelines increases, fewer and fewer patients will meet IMPROVE-IT criteria in clinical practice. In addition, trial patients were younger and considerably healthier than corresponding PINNACLE patients. In the world of clinical practice, clinicians must increasingly balance advanced age, multimorbidity, and polypharmacy with their treatment decisions. For trials to best inform clinical care, recruiting populations that more closely reflect these realities will be crucial.” – by Alaina Tedesco

Disclosure: The researchers report receiving support from the American College of Cardiology National Cardiovascular Data Registry.

Perspective

Did IMPROVE-IT Prove It?

The IMPROVE-IT trial compared simvastatin with ezetimibe to simvastatin therapy alone in 18,144 patients with acute coronary syndromes (ACS).Median LDL cholesterol was significantly lowered by the addition of ezetimibe (69.5 vs. 53.7 mg per deciliter, p < 0.001). At 7 years, major cardiac events (MACE) occurred in 34.7% in the simvastatin monotherapy group compared with 32.7% in the simvastatin-ezetimibe group (p = 0.016). Combination therapy reduced the risk of nonfatal myocardial infarction, ischemic stroke, and urgent revascularization but not mortality.

The clinical relevance of the IMPROVE-IT trial is called into question by an analysis published in JAMA Internal Medicine. This study examined data from patients with ACS recorded in the American College of Cardiology practice innovation and clinical excellence (PINNACLE) registry. Only about one-third of PINNACLE registry patients with ACS would have qualified for enrollment in the IMPROVE-IT trial. Compared with the trial, PINNACLE patients were older, sicker, and received less intensive prevention therapies. The authors suggest that IMPROVE-IT is not representative of the general ACS population.

The question therefore remains: What is the role of ezetimibe in the management of patients with ACS? As the authors of the recent report note, a major deficiency of IMPROVE-IT that limits its relevance to current practice was the use of only a moderate-intensity statin. In contrast, contemporary guidelines recommend use of high-intensity statins (atorvastatin or rosuvastatin) for ACS.In the PROVE-IT trial, high dose atorvastatin resulted in a significant reduction in MACE within 2 years (26.3% vs. 22.4%). Thus, the risk reduction by atorvastatin monotherapy at 2 years was greater than that seen with simvastatin-ezetimibe combination therapy at 7 years.

The crucial question as to whether ezetimibe has incremental benefit when added to high-intensity statins remains unknown. Until this question is answered, ezetimibe for ACS will remain in prescription purgatory. Nevertheless, the IMPROVE-IT trial broke new ground by demonstrating that a nonstatin agent that lowers cholesterol can successfully lower the risk of cardiovascular events. Ezetimibe therefore represents a useful adjunctive option for those patients who are unable to tolerate or to achieve therapeutic goals on high dose, high-intensity statins.

References:

Cannon CP, et al. N Engl J Med. 2004;doi:10.1056/NEJMoa040583.
Cannon CP, et al. N Engl J Med. 2015;doi:10.1056/NEJMoa1410489.
Stone NJ, et al. J Am Coll Cardiol. 2014;doi:10.1016/j.jacc.2013.11.002.

Michael P. Savage, MD
Ralph J. Roberts Professor of Cardiology
Director Cardiac Catheterization Laboratory
Director Jefferson Angioplasty Center
Thomas Jefferson University Hospital
michael.savage@jefferson.edu
@DocSavageTJU

David L. Fischman, MD
Professor of Medicine
Co-Director Cardiac Catheterization Laboratory
Director Interventional Cardiology Fellowship Program
Thomas Jefferson University Hospital

Disclosures: Savage and Fischman report no relevant financial disclosures.

Sources/Disclosures

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Source: Maddox TM, et al. JAMA Intern Med. 2017;doi:10.1001/jamainternmed.2017.0754.