Evolution of the Lipid Trial Protocol of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial

https://doi.org/10.1016/j.amjcard.2007.03.024Get rights and content

The Action to Control Cardiovascular Risk in Diabetes (ACCORD) lipid trial aims to test whether a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) plus a fibrate is more efficacious in reducing cardiovascular events than a statin plus placebo in patients with type 2 diabetes mellitus with defined glycemic control. This is a blinded component in a 5,518-patient subset of the ACCORD cohort. These participants were randomized to either be (1) treated with simvastatin (titrated to 40 mg/day if necessary to achieve a goal low-density lipoprotein [LDL] cholesterol level of <2.59 mmol/L [100 mg/dL]) plus placebo or (2) treated to the same goal LDL cholesterol level with the statin plus active fenofibrate 160 mg/day or its bioequivalent (or 54 mg/day if the estimated glomerular filtration rate ranges from 30 to <50 mL/min per 1.73 m2). Setting an upper limit of LDL cholesterol qualifying for randomization excluded patients who would not likely achieve the LDL cholesterol goal. Recruitment for ACCORD began in January 2001, and follow-up is scheduled to end in June 2009. Since recruitment began, several clinical trials and consensus statements have been published that led to changes in the details of the lipid treatment algorithm and protocol. This report describes the design of the lipid protocol and modifications to the protocol during the course of the study in response to and in anticipation of these developments. The current protocol is designed to provide an ethically justifiable test of combined statin plus fibrate treatment consistent with the highest level of safety and lipid treatment standards of care.

Section snippets

Background: Overall Action to Control Cardiovascular Risk in Diabetes Design and the Lipid Trial Component

Details regarding the overall rationale and design of ACCORD in general can be found elsewhere in this supplement.1, 2 Briefly, the overall goal of the ACCORD trial is to test 3 complementary medical treatment strategies for reducing the rate of major CVD morbidity and mortality in type 2 diabetes mellitus. It was designed as a randomized, multicenter, double 2 × 2 factorial trial in 10,000 patients with type 2 diabetes. Ultimately, 10,251 participants were recruited. The trial is designed to

Rationale for the Action to Control Cardiovascular Risk in Diabetes Lipid Hypothesis

The design of ACCORD began in 1999. The guidelines for the management of dyslipidemia at the time were the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) II.3 These 1993 guidelines considered LDL cholesterol as the cornerstone of lipid management, but by 1999, they were outdated. In particular, the ATP II guidelines were formulated before the publication of results of the major statin trials, and they identified bile acid–binding resins as the drugs of first choice

Evolution of the Action to Control Cardiovascular Risk in Diabetes Lipid Protocol

As noted previously, recruitment and follow-up for ACCORD was divided into a vanguard phase (January 2001 to December 2002) and a main trial phase (February 2003 to June 2009). The vanguard phase evaluated recruitment and treatment strategies for all components of the trial, including the lipid component, before the institution of the full trial. Lessons learned from the vanguard phase were incorporated into the main trial protocol. Protocol changes in lipid trial eligibility and treatment made

Conclusion

One of the most important questions that could be asked about the pharmacologic management of dyslipidemia in patients with diabetes is whether combined therapy with a statin plus a fibrate offers an additional reduction of cardiovascular events beyond that of a statin alone, with an acceptable risk profile. The importance of this question is highlighted by the recent Simvastatin Plus Fenofibrate for Combined Hyperlipidemia (SAFARI) trial, evaluating lipid responses and the safety of

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    This work was supported by Contract Nos. N01-HC-95178, N01-HC-95179, N01-HC-95180, N01-HC-95181, N01-HC-95182, N01-HC-95183, N01-HC-95184, IAA #Y1-HC-9035, and IAA #Y1-HC-1010 from the National Heart, Lung, and Blood Institute (NHLBI), with additional support from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Eye Institute (NEI), the National Institute on Aging (NIA), and the Centers for Disease Control and Prevention (CDC). General Clinical Research Centers provide support at many sites.

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    A complete list of the names and affiliations of members of the ACCORD Study Group appears in the Appendix.

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