Applicability of the IMPROVE-IT Trial to Current Patients With Acute Coronary Syndrome: An NCDR Research to Practice Project

Clinical trials serve as the foundation for evidence-based cardiovascular practice, but maximize their value only if they address questions relevant to current practice. 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,¹ but it is unclear to what degree these results may impact clinical care.

The Research to Practice (R2P) initiative uses clinical registries to understand the relevance of clinical research to practice.² Under this initiative, we used data from the American College of Cardiology practice innovation and clinical excellence (PINNACLE) ambulatory cardiology practice registry to determine the proportion of current ACS patients that would have qualified for the IMPROVE-IT trial, and how their characteristics compared with trial participants.

Waiver of written informed consent and authorization for use of the PINNACLE registry were obtained. Both were granted by Chesapeake Research Review Incorporated. We identified recent patients with ACS recorded in the PINNACLE registry between January 2013 and September 2014. Consistent with IMPROVE-IT inclusion criteria, we excluded patients treated with high-intensity statins,³ younger than 50 years, or not meeting the trial’s baseline low-density lipoprotein cholesterol (LDL-C) enrollment criteria.¹ We also excluded patients with contraindications to statins or ezetimibe, triglyceride levels higher than 350 mg/dL, chronic liver or kidney disease, or concurrent therapy with verapamil, amiodarone, niacin, fibrates, ezetimibe, and/or 2 or more statin medications. Finally, we excluded all patients with a history of coronary artery bypass grafting.

We calculated the overall and practice-specific rates of PINNACLE patients meeting IMPROVE-IT enrollment criteria. We also compared the demographics, medical comorbidities, and medications of qualifying PINNACLE patients with those of the IMPROVE-IT trial population.¹ Racial and ethnicity classifications were based on patient self-reporting. Practice variation rates were reported as medians and interquartile ranges (IQR).

Between January 2013 and September 2014, 28 454 PINNACLE patients with ACS at 182 practices were identified. Of these, 10 228 (35.9%) met IMPROVE-IT criteria (Figure), with modest variation between practices (median 34.5%; IQR, 25.6-42.9). Compared with IMPROVE-IT patients, PINNACLE patients were significantly older, more likely female, had markedly higher rates of peripheral arterial disease, heart failure, and hypertension, and had lower rates of secondary prevention medication use (Table).

Only one-third of current patients with ACS would have qualified for the IMPROVE-IT trial, with modest practice variation. Compared with the trial population, qualifying PINNACLE patients were older, sicker, and received less optimal secondary prevention therapies. Thus, it is unclear if the effect seen with simvastatin/ezetimibe use in the trial translates to current patients with ACS.

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.³ 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.

There are limitations to our study. Our data may not fully capture all medication use or contraindications, so statin and other medication use may be underreported. PINNACLE practices may differ from nonparticipating practices, potentially limiting generalizability. Finally, PINNACLE is limited to US cardiology practices, and cannot speak to how the IMPROVE-IT trial may impact non-US clinical settings.

We found that the IMPROVE-IT trial population was not closely reflective of current clinical practice, calling into question the applicability of ezetimibe/simvastatin use to current patients with ACS. Strategies to more closely align trials with real-world patient characteristics are needed.

Corresponding Author: Thomas M. Maddox, MD, MSc, VA Eastern Colorado Health Care System, Cardiology Section (111B), 1055 Clermont St, Denver, CO 80220 (thomas.maddox@va.gov).

Accepted for Publication: January 23, 2017.

Published Online: April 24, 2017. doi:10.1001/jamainternmed.2017.0754

Author Contributions: Dr Maddox had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Maddox, Masoudi, Virani, Rumsfeld.

Acquisition, analysis, or interpretation of data: Maddox, Tang, Downs, Masoudi, Daugherty.

Drafting of the manuscript: Maddox.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Maddox, Tang.

Administrative, technical, or material support: Masoudi, Rumsfeld.

Conflict of Interest Disclosures: Dr Masoudi is the Chief Medical Officer for the National Cardiovascular Data Registry. Dr Rumsfeld is Chief Innovation Officer for the American College of Cardiology. No other disclosures are reported.

Funding/Support: This research was supported by the American College of Cardiology National Cardiovascular Data Registry. The PINNACLE Registry is an initiative of the American College of Cardiology. Bristol-Myers Squibb and Pfizer Inc are founding sponsors of the PINNACLE Registry.

Role of the Funder/Sponsor: The PINNACLE Registry and the National Cardiovascular Data Registry had no role in the design or conduct of the study, the management or analysis performed in the study, or the interpretation of the data. Before submission for publication, the manuscript was approved with minor editorial suggestions by the PINNACLE Registry Research and Publications Committee.

Disclaimer: The views expressed in this article represent those of the authors and do not necessarily represent the official views of the National Cardiovascular Data Registry or its associated professional societies identified at http://www.ncdr.com.

Additional Contributions: The authors thank Karen E. Joynt, MD, MPH, Brigham and Women’s Hospital, Boston, MA, for her review and edits of the article. She received no compensation.