Author + information
- Thomas M. Maddox, MD, MSc, FACC∗ (, )
- Frederick A. Masoudi, MD, MSPH, FACC,
- William J. Oetgen, MD, MBA, FACC, FACP and
- John S. Rumsfeld, MD, PhD, FACC
- ↵∗Address correspondence to:
Dr. Thomas M. Maddox, American College of Cardiology, 2400 N Street NW, Washington, DC 20037.
Randomized controlled trials (RCTs) remain a “gold standard” for evaluating treatment efficacy. Typically conducted in controlled environments with selected populations, RCTs can isolate the effect of a treatment on an outcome and largely eliminate confounding. Thus, positive RCTs, in the words of the philosopher Nancy Cartwright, support the claim that the studied treatment “works somewhere” (1). However, the results of RCTs alone are not sufficient to inform clinical practice decisions. We need to know if the studied treatments “will work for us” (1).
Will RCT interventions produce the desired outcomes in our own practice situation and among the patients we treat? RCT results are typically considered as a summary effect of the intervention among the study participants, and heterogeneity of this effect among individual patients is well characterized (2). In addition, the selected trial populations may not represent the typical population encountered in clinical practice, further complicating the translation of trial evidence to practice. Cartwright characterizes this challenge as a need to understand the “capacity” of the treatment, or its ability to reliably promote the outcome across the spectrum of circumstances and patients that we encounter in day-to-day practice. Evaluating the potential for RCT findings to translate to cardiovascular clinical practice is not consistently done, and such information is usually slow to emerge.
To address this issue, the National Cardiovascular Data Registry (NCDR) is launching the Rapid Registry Response (RRR) initiative. The RRR initiative will use clinical registry data to evaluate the implications of RCT findings on current clinical practice in a timely manner. Upon the release of important RCTs or new clinical practice guidelines, the RRR initiative will be poised to rapidly conduct analyses to determine their effect on care. These analyses will address questions such as the proportion of current patients in cardiology practices that would have been eligible for RCT enrollment, the size and characteristics of patient populations that were not eligible for trial enrollment, and prevalent comorbidities or other treatments that may modify the RCT treatment. In addition, insights from the initiative can also assist cardiac researchers in formulating research hypotheses for future studies. This ability of the initiative to have practice inform evidence generation fulfills a fundamental component of “learning healthcare systems” (3).
The RRR initiative will use the NCDR clinical registry programs to conduct these analyses. The NCDR registries, which include a variety of cardiology conditions and treatments, are some of the largest in the world and, by virtue of their size, account for a substantial portion of U.S. cardiology practice. In addition, the 2 ambulatory registries, PINNACLE and the Diabetes Collaborative Registry, capture data directly from electronic medical records, allowing for real-time assessment of the effect of new evidence on current care. By using the NCDR programs to fuel its analyses, the RRR initiative will provide comprehensive and timely assessments of the capacity of RCTs to translate to actual cardiology practice.
The recent IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial) provides an example of the potential of the RRR initiative (4). The trial demonstrated a modest reduction in cardiovascular events among patients with acute coronary syndromes (ACS) receiving ezetimibe in addition to a moderate-intensity statin (4). How do the results of this study apply to current cardiovascular practice? We can use NCDR PINNACLE data to examine the proportion of patients that might have been eligible for IMPROVE-IT enrollment, and thus could potentially benefit from the addition of ezetimibe to their medication regimens. In addition, we can determine the characteristics of those patients currently on moderate-intensity statin therapy but who would not have been eligible for the trial, to shed light on where clinicians will have to make decisions about whether trial results extrapolate to real-world patient populations.
We can also consider the implications of the IMPROVE-IT results on current practice. The most recent cholesterol guidelines, published a year before the release of the IMPROVE-IT trial results, recommended high-intensity statins for all ACS patients (5). In general, high-intensity statins achieve 20% additional lowering of low-density lipoprotein cholesterol (LDL-C) levels relative to moderate-intensity statins. This 20% additional reduction is very similar to the effect that ezetimibe had on LDL-C lowering in IMPROVE-IT. If, as the IMPROVE-IT investigators contend, the cardiovascular effect of ezetimibe was primarily mediated by its LDL-C–lowering effects, then its use in the setting of high-intensity statins might result in even lower LDL-C levels than those seen in the trial and, potentially, further reductions in adverse cardiac events. An RRR analysis of current statin practice patterns and the achieved LDL-C levels with high-intensity statin use among patients with ACS can provide insight into this possibility. Finally, the registry can help identify the patient populations that cannot tolerate high-intensity statins and that might thus be the optimal candidates for ezetimibe, or other lipid-lowering therapies such as PCSK9 inhibitors, as an adjunctive therapy.
Major RCTs and evidence syntheses with significant practice implications are released each year, both at the major cardiology meetings (e.g., the American College of Cardiology Scientific Sessions, the American Heart Association Scientific Sessions, and the European Society of Cardiology Congress) and in the published medical data. The RRR initiative will review this evidence and conduct complementary analyses to understand the capacity of this evidence to inform current practice. Initial efforts are already under way, with RRR analyses being conducted in conjunction with several RCTs released at the recent ACC Scientific Sessions. In this manner, the RRR initiative will provide a timely “real-world” perspective on the potential effect of the continually evolving body of evidence to inform current cardiovascular practice.
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