Relative risk of CV events similarly increased with resting heart rate irrespective of diabetes status

Resting heart rate and cardiovascular outcomes in diabetic and non-diabetic individuals at high cardiovascular risk analysis from the ONTARGET/TRANSCEND trials

Literature - Böhm M, Schumacher H, Teo KK et al., - Eur Heart J 2018, ehy808, https://doi.org/10.1093/eurheartj/ehy808

Introduction and methods

Diabetes is associated with an increased risk of CVD, especially when a patient also has hypertension [1]. Elevated blood pressure (BP) is associated with enhanced resting heart rate (RHR) in patients with diabetes [2], which in itself is a predictor of mortality and CVD in various populations. RHR is associated with various poor health conditions, including incident diabetes [3].

RHR is regulated by the autonomic nervous system and influenced by autonomic imbalance as a result of parasympathetic denervation and sympathetic overactivity in diabetes [4,5]. It is important to know whether high RHR contributes to the higher CVD risk in patients with diabetes, and whether RHR-lowering drugs can potentially modify the RHR-risk association and thus may be a therapeutic option.

The ONTARGET and TRANSCEND studies randomized 31.546patients with high CV risk to ramipril, telmisartan or their combination. 11.730 of those had diabetes and 19806 did not. This analysis aimed to assess the risk at different on-treatment RHR levels in patients with or without diabetes after prior stroke, myocardial infarction (MI), peripheral artery disease (PAD) and at high CV risk on contemporary treatments, using pooled data of ONTARGET and TRANSCEND. RHR and BP were taken after resting for 3 minutes in a sitting position, using an automated validated device, in the presence of the study nurse or investigator. Data of 30.937 patients were used for analysis, 19.450 of whom did not have diabetes, and 11.487 did.

In diabetes patients, on average 8.2 (±2.5) RHR measurements were taken over 54.3 (±11.8) months, and in those without diabetes a mean of 8.4 (±2.5) RHR measurements were done in 55.3 (±10.2) months. The primary composite outcome was composed of CV death, MI, stroke, and hospital admission for heart failure (HHF). Since outcomes were not different between treatment groups in ONTARGET and TRANSCEND, all outcome events were combined for this analysis. Diabetes and non-diabetes patients were categorized into subgroups according to baseline RHR and to their mean achieved in-trail RHR (<60 bpm, 60 to<65, 65 to <70, 70 to <75, 75 to <80 and ≥80 bpm).

Main results

  • Patients with diabetes had slightly higher mean in-trial RHR than those without (71.8 ± 9.0 vs. 67.9 ± 8.8, P<0.0001).
  • The primary outcome, and its components CV death, HHF and all-cause death were observed more often in patients with RHR ≥80 bpm. The difference in risk associated with higher RHR was less pronounced for MI and absent for stroke.
  • As compared with persons without diabetes with RHR 60-65 bpm, patients with diabetes showed a higher risk of the primary outcome, as did diabetes patients with RHR >75 bpm. No statistically significant interaction was found between presence of diabetes and achieved in-trial RHR for all outcomes.
  • Different non-linear relationships were observed between RHR and the CV outcomes. For both patients with and without diabetes, an increased risk of the primary outcome, HHF and all-cause death was see above a threshold of on-treatment RHR >75 bpm. For MI, a threshold of ≥80 bpm was seen, and there was no association with stroke.

Conclusion

This analysis of data of ONTARGET and TRANSCEND in patients at high CV risk, shows that the relative risk of CV outcomes associated with high RHRs is similar for patients with and without diabetes. Across the spectrum of RHR, absolute event rates are, however, higher in patients with diabetes, and RHR is also higher in those with diabetes. The risk associations of RHR and outcomes varied per type of outcome; strongest for the primary composite outcome, HHF and all-cause death, and were less pronounced for MI and absent for stroke.

References

1. Ferrannini E, Cushman WC. Diabetes and hypertension: the bad companions. Lancet 2012;380:601–610.

2. Ferrannini E, Balkau B, Coppack SW, et al. Insulin resistance, insulin response, and obesity as indicators of metabolic risk. J Clin Endocrinol Metab 2007;92:2885–2892.

3. Carnethon MR, Yan L, Greenland P, et al Resting heart rate in middle age and diabetes development in older age. Diabetes Care 2008;31:335–339.

4. Kuehl M, Stevens MJ. Cardiovascular autonomic neuropathies as complications of diabetes mellitus. Nat Rev Endocrinol 2012;8:405–416.

5. Xuan YL, Wang Y, Xue M, et al. In rats the duration of diabetes influences its impact on cardiac autonomic innervations and electrophysiology. Auton Neurosci 2015;189:31–36.

Find this article online at Eur Heart J

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