Expert panel discussion
Heart rate as a risk factor in cardiovascular disease Gordon McInnes BSc(Hons), MD, FRCP, FFPM, FBPharmacolS, Sandosh Padmanabhan PhD, MD, FRCP and Ian Menown MD, FRCP Resting heart rate has been shown in many studies to be an independent risk factor postMI, in stable coronary artery disease and in heart failure. Despite this, heart rate is often not measured or considered when managing patients with cardiovascular disease. In this Expert Panel Discussion, the panel looks at the evidence for the association between heart rate and cardiovascular risk, and discusses current management guidelines and how the focus on this risk factor could be increased.
Gordon McInnes, professor of clinical pharmacology, Division of Cardiovascular and Medical Sciences, Gardiner Institute, Glasgow
Sandosh Padmanabhan, clinical senior lecturer and honorary consultant physician, BHF Glasgow Cardiovascular Research Centre, University of Glasgow
Ian Menown, consultant cardiologist, Craigavon Cardiac Centre, Southern Trust, Northern Ireland
GORDON MCINNES: Sandosh, could you start by
telling us about the evidence of the association between heart rate and cardiovascular risk? SANDOSH PADMANABHAN: Heart rate has long
been recognised as a risk factor. Many observational epidemiological studies have shown that an increased resting heart rate tends to be associated with increased cardiovascular risk. The Framingham study showed that an increase in heart rate of 10 beats per minute (bpm) was associated with an increase in all-cause mortality and cardiovascular mortality.1 It also showed that resting heart rate was an independent risk factor in hypertensive patients.2 The Systolic Hypertension in Europe study, in older patients, also suggested a trend towards heart rate being a predictor of all-cause cardiovascular and noncardiovascular mortality. 3 The International www.prescriber.co.uk
Verapamil-SR/trandolapril Study (INVEST) looked at the heart rate in hypertensive patients with coronary artery disease and found a J-shaped relationship, with an increased risk at both the lower and the higher ends of the heart rate distribution.4 However, this study included patients with underlying risk factors and associated co-morbidities. We have studied approximately 11 000 patients attending the Glasgow Blood Pressure Clinic, who have been followed up for more than 20 years.5 We have allcause mortality data and repeated heart rate and blood pressure measurements, representative of a cross-section of the hypertensive population with a range of blood pressures from mild to severe. We looked at heart rate at baseline, when the patient first visited the clinic, and also the achieved heart rate during follow-up. We showed that there was an almost linear relationship between heart rate and mortality; we also found that the achieved heart rate was a better predictor of risk than the baseline heart rate. An even better predictor of risk was if the heart rate changed over time. We showed that patients whose heart rate increased during follow-up were at much higher risk than those whose heart rate remained low or decreased during follow-up. IAN MENOWN: Over the past 25 years, there have
been many epidemiological studies of apparently well This Expert Panel Discussion was supported through an educational grant from Servier. Servier provided funding to cover administrative, logistical and editorial support and reviewed the manuscript for technical accuracy. Editorial control resided with the panel members and the publisher.
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Expert panel discussion
populations that have demonstrated a relationship between resting heart rate and the risk of subsequent cardiovascular mortality. While the relationship between resting heart rate and risk is continuous, it may be of practical value to try to identify a heart rate threshold from the studies above which there is a significant increase in risk. One interesting paper from Jouven et al, which followed apparently well subjects for 23 years, found that the risk of sudden death from MI was increased in subjects with a resting heart rate >75 bpm.6 The INVEST trial, in patients with hypertension, suggested a statistically significant increase in risk beginning at 75 bpm.4 Another important trial, this time in patients with stable coronary artery disease, was an analysis of almost 25 000 patients from the Coronary Artery Surgery Study (CASS) registry.7 A resting heart rate of >80 bpm was associated with an increase in risk of both overall and cardiovascular mortality, even after adjustment for all the expected predictors of risk such as age, sex, cardiovascular risk factors, drugs and ejection fraction. In the BEAUTIFUL study, patients with resting heart rate >70 bpm had a 34 per cent increase in risk of cardiovascular death.8 There is also a wealth of heart rate data from patients with acute coronary syndromes. From the prethrombolytic era, we have numerous studies from Stockholm, and also the SPRINT 2 data, describing the association between heart rate and risk following admission with acute MI.9 In the reperfusion era, various studies, for example GISSI-3 and GUSTO-1,10,11 published data showing the relationship between heart rate on admission, discharge and follow-up and subsequent risk. While it can be argued that it is hard to fully control for statistical confounders of admission heart rate such as pulmonary oedema (a strong predictor of subsequent mortality), the demonstration of increased risk associated with elevated heart rate at discharge or follow-up is of particular interest and importance. The GISSI-3 Prevenzione study12 showed that a resting heart rate of >75 bpm at follow-up was an independent predictor for mortality. GORDON MCINNES: That is a ver y important point – this is not just something that we see in the general or hypertensive population, but in people who have established coronary and cardiovascular disease. An Italian study has shown that a high heart rate predicts high blood pressure. 13 The INVEST study included treated patients, which might confound the 46
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analysis. A large Norwegian study of nearly 400 000 people found a strong relationship in both men and women between resting heart rate and mortality and cardiovascular disease, but this was greatly diminished when corrections were made for other risk factors.14 Is resting heart rate really a risk factor or is it just an indicator of risk? IAN MENOWN: To answer this question we need to examine studies that looked at the effect of starting a heart rate-lowering strategy. Intravascular ultrasound (IVUS) data from Nissen’s group15 showed significant reduction in coronary atheroma volume comparing baseline with 18-month IVUS imaging in those receiving beta-blockers (n=1154) adjusting for relevant confounders, but not in those not receiving beta-blockers (n=361). The BCAPS study showed significantly less carotid intima-media thickness progression after heart rate reduction.16 There are also data suggesting that heart rate reduction per se rather than a unique betablocker benefit is of importance. Interesting subgroup data from the Göteborg Metoprolol Trial showed that metoprolol intervention was beneficial for heart rate >70 bpm,17 but not significantly better than placebo with heart rate 80/85 bpm at discharge as being suboptimally controlled. One of the limitations of beta-blockade has been failure to tolerate older drugs. We now have bisoprolol and nebivolol, which are better tolerated and are sometimes used at small doses even in patients with COPD. The question is, does the beta-blocker lower the heart rate enough? There is now evidence to support the safety of combining beta-blocker and ivabradine to try and achieve a lower heart rate. If patients genuinely cannot tolerate any beta-blockade, conventional practice has been to give rate-limiting calcium-channel blocker monotherapy, although these are contraindicated if the ejection fraction is impaired (
