Effects of cardiac autonomic dysfunction on mortality risk in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial

Rodica Pop-Busui, Gregory W Evans, Hertzel C Gerstein, Vivian Fonseca, Jerome L Fleg, Byron J Hoogwerf, Saul Genuth, Richard H Grimm, Marshall A Corson, Ronald Prineas, Action to Control Cardiovascular Risk in Diabetes Study Group, Rodica Pop-Busui, Gregory W Evans, Hertzel C Gerstein, Vivian Fonseca, Jerome L Fleg, Byron J Hoogwerf, Saul Genuth, Richard H Grimm, Marshall A Corson, Ronald Prineas, Action to Control Cardiovascular Risk in Diabetes Study Group

Abstract

Objective: Intensive therapy targeting normal blood glucose increased mortality compared with standard treatment in a randomized clinical trial of 10,251 participants with type 2 diabetes at high-risk for cardiovascular disease (CVD) events. We evaluated whether the presence of cardiac autonomic neuropathy (CAN) at baseline modified the effect of intensive compared with standard glycemia treatment on mortality outcomes in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial participants.

Research design and methods: CAN was assessed by measures of heart rate variability (HRV) and QT index (QTI) computed from 10-s resting electrocardiograms in 8,135 ACCORD trial participants with valid measurements (mean age 63.0 years, 40% women). Prespecified CAN definitions included a composite of the lowest quartile of HRV and highest QTI quartile in the presence or absence of peripheral neuropathy. Outcomes were all-cause and CVD mortality. Associations between CAN and mortality were evaluated by proportional hazards analysis, adjusting for treatment group allocation, CVD history, and multiple prespecified baseline covariates.

Results: During a mean 3.5 years follow-up, there were 329 deaths from all causes. In fully adjusted analyses, participants with baseline CAN were 1.55-2.14 times as likely to die as participants without CAN, depending on the CAN definition used (P < 0.02 for all). The effect of allocation to the intensive group on all-cause and CVD mortality was similar in participants with or without CAN at baseline (P(interaction) > 0.7).

Conclusions: Whereas CAN was associated with increased mortality in this high-risk type 2 diabetes cohort, these analyses indicate that participants with CAN at baseline had similar mortality outcomes from intensive compared with standard glycemia treatment in the ACCORD cohort.

Trial registration: ClinicalTrials.gov NCT00000620.

Figures

Figure 1
Figure 1
A: Effects of CAN and glycemia intervention on all-cause mortality: HRs adjusted for treatment allocation and baseline age, sex, ethnicity, diabetes duration, A1C, BMI, SBP and DBP, LDL cholesterol, triglycerides, microalbumin-to-creatinine ratio, CVD history, and use of TZDs, insulin, β-blockers, ACE inhibitors/angiotensin receptor blockers, statins, alcohol, and cigarettes. B: Effects of CAN and glycemia intervention on CVD mortality: HRs adjusted for treatment allocation and baseline age, sex, ethnicity, diabetes duration, A1C, BMI, SBP and DBP, LDL cholesterol, triglycerides, microalbumin-to-creatinine ratio, CVD history, and use of TZDs, insulin, ACE inhibitors/angiotensin-receptor blockers, β-blockers, statins, alcohol, and cigarettes. CAN1 was defined as the lowest quartile of SDNN, and the highest quartile of QTI, CAN2 as the lowest quartile of SDNN, the highest quartile of QTI, and the highest quartile of heart rate, and CAN3 as the lowest quartile of SDNN and the highest quartiles of QTI and heart rate in the presence of DPN.

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