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Prognostic value of resting heart rate in patients with stable coronary artery disease, from the randomised, double-blind, placebo-controlled, multicentre EUROPA trial.

Clinical Trial Update II

Chronic Ischaemic Heart Disease (IHD)

Presenter report:

Ferrari, Roberto (Italy)


Background: There is increasing evidence that elevated resting heart rate (HR) is associated with increased mortality in patients with stable coronary artery disease (CAD). In the EUropean trial on Reduction Of cardiac events with Perindopril in patients with stable coronary Artery disease (EUROPA), 12,218 patients with established CAD without evidence of heart failure receiving standard preventive therapy, were treated with perindopril 8 mg/day or placebo for a mean of  4.2 years.


Objective and methods: To explore the impact of baseline HR on outcomes in patients with stable CAD receiving optimal therapy by comparing two subgroups (baseline resting HR<75 and ≥75 bpm) using a Cox proportional hazards model with adjustment for cardiovascular risk factors and treatment, and allocation to perindopril or placebo.


Results: HR data were available for 12,205 patients. Resting HR ≥75 bpm (n=3134) was associated with 21% (P<0.05), 24% (P<0.05), and 51% (P=0.013) increases in relative risk for total mortality, cardiovascular mortality, and hospitalisation for heart failure over 4.2 years. The HR ≥75 bpm subgroup had greater relative risk for the composite end point of hospitalisation for heart failure and/or cardiovascular mortality (23%, P=0.025). The predictive value of resting HR remained strong after adjustment for baseline characteristics, treatments, and the other risk parameters analysed.


Conclusions: These results suggest that resting HR is a powerful predictor of mortality and hospitalisation for heart failure in patients with stable CAD. Therefore, HR should be used for risk stratification and management of patients with stable CAD.

Discussant report:

Danchin, Nicolas


In this EUROPA trial analysis, Prof. Ferrari showed that patients with a heart rate ≥75 bpm had worse clinical outcomes than those with a lower heart rate (HR).

These results concur with some, but not all previous studies in patients with coronary artery disease. In particular, in the ACTION trial, a trial contemporary to EUROPA and in a very similar population with no known left ventricular dysfunction, HR was not recognized as an independent predictor of survival.

The mechanisms by which a lower HR could improve outcomes are not fully elucidated. In a small angiographic study, increased HR was an independent correlate of plaque rupture (Heidland and Strauer, Circulation 2001).

This mechanism, however, is not a likely explanation for the EUROPA findings since only fatal myocardial infarctions were increased in patients with a higher HR, while there was no impact on non-fatal infarctions. Another possibility is that increased HR could promote LV failure, or could reflect subclinical LV dysfunction. In keeping with this hypothesis, there were more heart failure hospitalizations in patients with increased HR.

To determine whether HR could be a marker of outcomes independently of LV function, adjustment on LVEF would have been needed, but this information was not available in the present study. Finally, other mechanisms, such as a catecholergic imbalance, might also be involved. 


Overall, these results indicate that increased HR is a marker of future cardiovascular events: clinicians should therefore pay attention to this simple clinical sign. Whether increased HR is only a marker of risk, or an independent risk factor will need further studies that can be envisaged now that medications acting as pure HR lowering agents are available.  


Heidland UE, Strauer BE.
Left ventricular muscle mass and elevated heart rate are associated with coronary plaque disruption.
Circulation 2001;104(13):1477-82.




Clinical Trial Update II

Notes to editor

This congress report accompanies a presentation given at the ESC Congress 2008. Written by the author himself/herself, this report does not necessarily reflect the opinion of the European Society of Cardiology.

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.