Generalizability of the REDUCE-IT trial and cardiovascular outcomes associated with hypertriglyceridemia among patients potentially eligible for icosapent ethyl therapy: An analysis of the REduction of Atherothrombosis for Continued Health (REACH) registry
Graphical abstract
Introduction
Epidemiological studies suggest that in the general population both moderate and severe hypertriglyceridemia are associated with increased long term cardiovascular (CV) risk and mortality. [1], [2] In patients with established CV disease, there is also evidence of a higher CV risk in patients with elevated triglycerides (TG). [3], [4], [5], [6] The randomized Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT) recently enrolled 8179 statin-treated patients with elevated TG levels (≥135 mg/dL and < 500 mg/dL) and either established CV disease or diabetes plus at least one risk factor, and demonstrated that a high dose (4 g/day) of icosapent ethyl reduced the risk of ischemic events, including CV death. [7], [8] Based on these results, the National Lipid Association recommended treatment with icosapent ethyl for patients aged ≥45 years with clinical atherosclerotic cardiovascular disease (ASCVD), or aged ≥50 years with diabetes mellitus requiring medication plus ≥1 additional risk factor, with fasting TG 135 to 499 mg/dL on high-intensity or maximally tolerated statin therapy with or without ezetimibe, (evidence rating: class I; evidence level: B-R). [9] The European Society of Cardiology guidelines also recommend icosapent ethyl (2x2g/day) in combination with a statin in high-risk (or above) patients with TG levels between 135 and 499 mg/dL despite statin treatment (evidence rating: class IIa; evidence level: B). [10] Notwithstanding affordability and availability (i.e., access issues), a common problem in translating evidence acquired from randomized controlled trials into clinical practice is the applicability of trial results and in particular the proportion of patients who would qualify for treatment. [11] Therefore, it is important to assess the applicability of the REDUCE-IT trial population in a non-selected cohorts of patients with or at risk of ASCVD. Preliminary assessment of eligibility to REDUCE-IT reported that 15–25% of patients would be eligible to icosapent-ethyl for secondary prevention. [12] Nevertheless, these cohorts only evaluated patients with ASCVD.
The Reduction of Atherothrombosis for Continued Health (REACH) registry [13], [14], [15], [16] is a large international cohort of patients with stable atherothrombosis (either coronary artery disease [CAD], peripheral artery disease [PAD], or cerebrovascular disease [CVD]) or at risk of atherothrombosis due to multiple risk factors. This registry enrolled the two types of patients screened for enrollment in the REDUCE-IT trial: patients with established atherothrombosis and primary prevention patients with diabetes. Using data from REACH, we sought to evaluate what proportion of patients with atherothrombosis or with diabetes would be potentially eligible for enrollment in REDUCE-IT. Additional goals were to describe the reasons for ineligibility, and to compare the clinical characteristics and outcomes of REDUCE-IT Eligible REACH patients to those who where not eligible and to those excluded because of low TG.
Section snippets
REACH registry
The design of the REACH registry has been previously described. [13], [14], [15], [16] Briefly, REACH was a large prospective, observational, international registry of patients at least 45 years old, with either established atherosclerotic disease (CAD, PAD or CVD) or with at least three atherosclerotic risk factors. Detailed selection criteria are provided in the REACH trial. [13], [14], [15], [16]
More than 65,000 outpatients from 44 countries were included from December 2003 until June 2004,
REDUCE-IT eligible population among REACH participants
Among the 65,531 patients enrolled in REACH, 54,046 had ASCVD, 8418 had diabetes with a total of 62,464 included patients. Among the primary prevention cohort, 1036 patients (12.3%) would have been eligible for inclusion in REDUCE-IT. In the secondary prevention cohort, 6049 patients (11.2%) would have been eligible for inclusion in REDUCE-IT (Fig. 1). Overall, in the total cohort, 7085 patients (11.3%) would have been eligible for inclusion in REDUCE-IT. Among those not eligible in the primary
Discussion
Our study was designed to evaluate the proportion of patients which could be eligible for emerging strategies to reduce TG among individuals followed for ASCVD or high-risk of ASCVD. The REACH registry provided a large, internationally representative sample of stable outpatients with or at risk of atherothrombosis, with prolonged follow-up. Our analyses demonstrate that in a large international registry, 11.3% of patients with ASCVD or at high-risk of ASCVD met the REDUCE-IT inclusion criteria,
Study strengths and limitations
The REACH registry consists of a large, international representative sample of stable outpatients with or at risk of atherothrombosis, with prolonged follow-up. However, there are some limitations to our findings. First, REACH patients were enrolled in 2003–04, several years earlier than REDUCE-IT patients, and during that interval there have been significant improvements in the use of optimal medical therapies and in outcomes of patients with atherosclerosis. Indeed, patients were less
Conclusions
In a large international registry of patients with ASCVD or high risk of ASCVD and diabetes, mimicking the REDUCE-IT population, 11.3% of patients with ASCVD or at high-risk of ASCVD actually met the REDUCE-IT inclusion criteria, thus being eligible for treatment with icosapent ethyl to reduce CV risk. Eligible patients in REACH were found at higher risk of cardiac atherothrombotic events than non-eligible patients, reflected by a higher risk of PCI and CABG. Indeed, eligible patients in REACH
Relationship with industry
FP reports speaking, research and consulting fees from Biotronik, BBraun, Sanofi, Bayer and Bristol-Myers Squibb.
DB serves as the Chair and International Principal Investigator for REDUCE-IT, with research funding from Amarin to Brigham and Women's Hospital. DB discloses the following relationships - Advisory Board: Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, Janssen, Level Ex, Medscape Cardiology, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado
Acknowledgements
This study was in part supported by Amarin Pharma. The REACH Registry was sponsored by Sanofi-Aventis, Bristol-Myers Squibb, and the Waksman Foundation (Tokyo, Japan). The REACH Registry is endorsed by the World Heart Federation.
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