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© The European Society of Cardiology 2007. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Pure heart rate reduction: further perspectives in heart failure

Karl Swedberg

Department of Emergency and Cardiovascular Medicine, Sahlgrenska University Hospital/Östra, Sahlgrenska Academy, Göteborg University, Göteborg, Sweden

Corresponding author. Tel: +46 313 434 066; fax: +46 312 589 33. E-mail address: karl.swedberg{at}gu.se


   Abstract
Top
 Abstract
Introduction
 Rationale for the benefits...
 Proven benefits of heart...
 Further perspectives in heart...
 Conclusion
 References
 
In patients with symptomatic chronic heart failure, treatment with a beta-blocker has been shown to reduce mortality and sudden cardiac death, and major heart failure guidelines strongly recommend this treatment (Class I level of evidence A). It is believed that at least part of their benefit is related to their effect on heart rate. Many heart failure patients, however, still do not receive a beta-blocker, probably because the side effects of these agents limit their use in some, otherwise eligible, subjects. Furthermore, up-titration of beta-blockers is also suboptimal because of the resultant side effects, such as hypotension and fatigue. Medication that has heart rate-lowering properties similar to those of beta-blockers but without their side effects is, therefore, desirable for patients with heart failure.

Ivabradine, a heart rate-lowering agent that acts specifically on the If current of cardiac pacemaker cells in the sinus node without affecting other cardiac ionic currents, offers a new therapeutic possibility in heart failure. Several studies have shown that ivabradine has a unique pharmacodynamic profile, as it results in heart rate reduction without vasodilation or negative inotropic effects, and has been found to have beneficial effects on cardiac remodelling, capillary density, and left ventricular dysfunction. The ongoing SHIFT trial will assess the prognostic value of pure heart rate reduction in heart failure patients.

Key Words: Heart failure • If current • Heart rate • Left ventricular dysfunction


   Introduction
Top
 Abstract
 Introduction
Rationale for the benefits...
 Proven benefits of heart...
 Further perspectives in heart...
 Conclusion
 References
 
In Europe, the population of patients with heart failure is estimated to exceed 10 million from a total population of 900 million.1,2 Heart failure is a frequent cause of hospitalization, and it is estimated in Europe to be responsible for 1 million hospitalizations per year. In the Euro Heart Failure Survey, a quarter of patients hospitalized for heart failure were readmitted within 12 weeks of discharge from hospital.3 The burden of this condition is likely to increase over the coming decades as a result of an ageing population and improved survival rates in cardiac patients due to modern therapeutic innovations—particularly after acute myocardial infarction.4

Increased resting heart rate has recently received attention regarding its ability to be an independent prognostic factor in both the general population5,6 and in patients with coronary artery disease (CAD) or heart failure.7,8 Heart rate reduction has been found to be beneficial in patients with CAD for prevention of angina and improvement of their prognosis.9 As the natural history of patients with CAD includes the possible occurrence of acute myocardial infarction, progression towards heart failure, and death from a cardiovascular origin, heart rate reduction represents an attractive new approach to improving the prognosis of patients with heart failure.


   Rationale for the benefits of heart rate reduction in heart failure
Top
 Abstract
 Introduction
 Rationale for the benefits...
Proven benefits of heart...
 Further perspectives in heart...
 Conclusion
 References
 
A number of factors support the benefit that may be derived from heart rate reduction in heart failure. It is well established that heart rate is a regulating factor in myocardial oxygen demand. Factors that can affect myocardial oxygen demand include wall stress, which is dependent on preload and afterload, myocardial contractility, and heart rate. As reported many years ago by Holmberg and Varnauskas,10 myocardial oxygen uptake increases as a product of heart rate and systolic blood pressure in a linear fashion. If only heart rate is considered, the relationship is linear up to a heart rate of 100 beats per minute (bpm), and then the slope is less steep up to the maximum heart rate tested of 150 bpm.

On the other hand, the level of heart rate reflects the interactions of the adrenergic drive and vagal tone. The autonomic nervous system plays an important role in the development of atherosclerosis and is known to be an acute trigger of sudden cardiac death that accounts for a high proportion of heart failure-related mortality.


   Proven benefits of heart rate reduction in heart failure
Top
 Abstract
 Introduction
 Rationale for the benefits...
 Proven benefits of heart...
Further perspectives in heart...
 Conclusion
 References
 
Heart rate reduction has been found to be beneficial in several clinical situations, including angina pectoris, acute coronary syndromes, myocardial infarction, and heart failure.

Beta-blockers have been shown to reduce total mortality and sudden cardiac death and to improve event-free survival in symptomatic heart failure patients.11–18 In post-myocardial infarction patients, it is believed that at least part of the benefit of beta-blockers is related to their effect on heart rate.9 A multivariate analysis of the Cardiac Insufficiency BIsoprolol Study-II (CIBIS II),19 which used bisoprolol in patients with chronic heart failure, showed that the change in heart rate observed between baseline and the follow-up visit carried out 2 months after randomization was significantly related to survival and hospitalization in those heart failure patients in sinus rhythm. The study included 1268 patients in the placebo group and 1271 in the bisoprolol group, with each group comprising 1004 patients in sinus rhythm. Patients were subdivided into tertiles of distribution of heart rate: for baseline rates (Figure 1), ≤ 72 bpm, between 72 and ≤ 84 bpm, and > 84 bpm, and for heart rate changes at 2 months (Figure 2), < 0 bpm (heart rate increase), between ≥ 0 and < 11 bpm (moderate heart rate reduction), and ≥ 11 bpm (great heart rate reduction). In the three tertiles, the 1 year mortality was lower in the bisoprolol group than in the placebo group. As shown in Figure 2, the greatest heart rate decrease was seen in the bisoprolol group, and it was associated with the highest survival rates and the lowest number of hospital admissions. This study clearly shows that patients with heart failure in sinus rhythm who have the lowest initial heart rate and the greatest heart rate reduction at 2 months, will have the best prognosis. In the Carvedilol Or Metoprolol European Trial (COMET), the influence of heart rate, systolic blood pressure, and beta-blocker dose was evaluated in terms of outcome in 2599 out of 3029 patients who were alive and who remained on the study drug 4 months after randomization.20 Multivariate analysis showed that beta-blocker dose, heart rate, and systolic blood pressure achieved during beta-blocker therapy had an independent prognostic value in heart failure. Heart rate values above 68 bpm carried a highly significant (P< 0.0001) increased risk of heart failure compared with heart rates of < 68 bpm. Thackray et al.21 postulated that heart rate lowering is central to the beneficial effect of beta-blockade. In order to demonstrate this concept, they randomized 49 pacemaker-dependent patients with left ventricular systolic dysfunction (an ejection fraction lower than 40%) to either a chronic higher-paced heart rate group (80 pulses per minute) or a lower-paced heart rate group (60 pulses per minute). A total of 85% of patients had CAD, and the two groups of patients were receiving similar maintenance doses of carvedilol. The primary outcome was change in left ventricular volume (as a marker of beneficial reverse remodelling) from baseline to follow-up. During a mean follow-up period of 14 ± 13 months, 21 patients (43%) died and 25 (51%) completed the study protocol—12 in the higher heart rate group and 13 in the lower heart rate group. Mean left ventricular end-diastolic and systolic volumes increased with higher-rate versus lower-rate pacing, whereas left ventricular ejection fraction significantly declined with higher-rate pacing (P = 0.002). The authors concluded that reversal of beta-blocker-induced bradycardia has deleterious effects on ventricular function, suggesting that heart rate reduction is an important mediator of their effects. In a follow-up of an observation of the importance of heart rate reduction after an acute myocardial infarction, Kjekshus et al.22 in beta-blocker outcomes studies observed a relationship between the reduction in resting heart rate and the reduction in mortality (Figure 3).


Figure 1
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  		Figure 1 1 year mortality with SD (Kaplan-Meier estimate) according to baseline heart rate and study treatment group. Patients were divided into tertiles of distribution of heart rate change over entire population. Bars indicate SD. From Lechat et al.19 reference with permission.

 

Figure 2
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  		Figure 2 Distribution of patients according to heart rate after 2 months in CIBIS II trial. Patients were divided into tertiles of distribution of heart rate over entire population. From Lechat et al.19 reference with permission.

 

Figure 3
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  		Figure 3 Relationship Between Reduction of Resting Heart Rate and Reduction in Mortality From Beta-blocker Trials. From J Kjekshus et al.22 reference with permission.

 
We have compared the major guidelines on heart failure.23 The European Society of Cardiology, the American College of Cardiology/American Heart Association (ACC/AHA) 2005 Guideline Update, the Canadian Cardiovascular Consensus, and the Heart Failure Society of America 2006 Practice Guideline all have a consistent class I recommendation for the use of beta-blockers in heart failure, with a level of evidence classified as A, as for angiotensin-converting enzyme inhibitors. There are differences in their recommendations regarding angiotensin receptor blockers.

In summary, heart rate is an important factor in the regulation of myocardial oxygen consumption and an important prognostic factor, both in the general population and in patients with heart failure. Heart rate reduction with the use of heart rate-lowering agents, such as beta-blockers, is beneficial, and it is believed that the most important factor in the effect of beta-blockers is heart rate reduction. However, many heart failure patients still do not receive beta-blockers, probably because the side effects of these agents limit their use in some otherwise eligible patients.24 The contraindication of beta-blockers in patients with asthma, hypotension, atrioventricular conduction disorders, together with their negative inotropic effect and the common occurrence of side effects, are among the main reasons for lack of use. In heart failure, the uptitration of beta-blockers is also suboptimal because of side effects such as hypotension and fatigue. Therefore, a medication that has heart rate-lowering properties similar to those of beta-blockers, but is devoid of their side effects, is desirable in patients with heart failure.


   Further perspectives in heart failure: pure heart reduction
Top
 Abstract
 Introduction
 Rationale for the benefits...
 Proven benefits of heart...
 Further perspectives in heart...
Conclusion
 References
 
Ivabradine is the first selective If inhibitor to have been approved, thus inaugurating a new class of heart rate-lowering agents that act specifically on the sinoatrial node. Ivabradine inhibits the If current of cardiac pacemaker cells in the sinus node without affecting other cardiac ionic currents. It has a unique pharmacodynamic profile, as it results in heart rate reduction without vasodilating, negative inotropic and lusitropic effects. Ivabradine has also been found to have beneficial effects on cardiac remodelling, capillary density, and left ventricular dysfunction.25

Postsystolic wall thickening (PSWT) is part of a thickening that occurs after end-systole, and it represents wasted effort, as it does not contribute towards ejection. Lucats et al.26 used sonomicrometry to compare the effects of two heart rate-reducing agents—the beta-blocker atenolol and the selective If current inhibitor ivabradine—on PSWT in six dogs. Atenolol, but not ivabradine, caused a decrease in contractility, as measured by dP/dtmax. For a similar heart rate reduction at rest and during exercise, ivabradine did not alter PSWT and preserved the part of thickening contributing to ejection. Mulder et al.25 used a rat model of post-myocardial infarction congestive heart failure, involving coronary ligation, and showed that the chronic administration of ivabradine induced a dose-dependent reduction in heart rate without modification of systemic haemodynamics. Cardiac output was preserved despite the decrease in heart rate, because stroke volume was increased as a result of a decrease in left ventricular end-systolic diameter (Figure 4). Moreover, in a dose-dependent manner, ivabradine prevented the deterioration of left ventricular fractional shortening observed with time in untreated animals after 30 and 90 days. This improvement in left ventricular function was ascribed by the authors to a possible modification of left ventricular structure and/or myocyte properties. Furthermore, after 90 days of therapy, ivabradine significantly reduced noradrenaline levels by 15% and 16% at 3 mg and 10 mg kg–1 day–1, respectively. Manz et al.27 investigated the effect of ivabradine on left ventricular systolic function in patients with regional or global left ventricular dysfunction randomized to receive ivabradine 0.25 mg/kg (n = 31) or placebo (n = 13) by intravenous infusion. A single intravenous dose of ivabradine produced a substantial reduction in resting heart rate (17.6 ± 4.7%) without affecting left ventricular function.


Figure 4
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  		Figure 4 Beneficial effects of ivabradine on left ventricular function in heart failure. Reproduced from Mulder et al.26 reference with permission.

 
Jondeau et al.28 investigated the potential benefit and tolerability of ivabradine when administered to patients with stable class II heart failure associated with CAD, who were receiving treatment with angiotensin-converting enzyme inhibitors, diuretics, and—when indicated—digoxin. The study showed that ivabradine was safe and well tolerated during the 3-month follow-up period. If anything, left ventricular ejection fraction showed a trend towards improvement. De Ferrari et al.29 reported that following a 3 hour infusion of ivabradine, heart rate decreased from 93 to 82 bpm 4 hours after the onset of infusion, whereas stroke volume increased. Despite the marked heart rate reduction, cardiac output was preserved thanks to a marked increase in stroke volume.

The Systolic Heart failure treatment with the If inhibitor ivabradine Trial (SHIFT) is a multicentre, randomized, international, double-blind placebo-controlled trial in patients with moderate to severe heart failure, which aims to investigate the effect of ivabradine (7.15 mg twice daily) compared with placebo on the composite of cardiovascular death or hospitalization for new onset or worsening heart failure.30 Each arm of the study will include 2750 patients with a heart rate ≥ 70 bpm and a left ventricular ejection fraction of less than 35%.


   Conclusion
Top
 Abstract
 Introduction
 Rationale for the benefits...
 Proven benefits of heart...
 Further perspectives in heart...
 Conclusion
References
 
In order to reduce the mortality and morbidity of heart failure, which represents a major disease burden in Europe, new strategies are required. Among the new perspectives in heart failure management, pure heart rate reduction with ivabradine offers a promising approach. Ivabradine reduces heart rate without negatively affecting systemic haemodynamics. It has beneficial effects on left ventricular function and cardiac remodelling and it is well tolerated and safe. The ongoing SHIFT trial will assess the effects on outcomes of pure heart rate reduction in heart failure patients.

Conflict of interest: Received honoraria and research support from Astrazeneca, Roche and Servier.


   References
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 Abstract
 Introduction
 Rationale for the benefits...
 Proven benefits of heart...
 Further perspectives in heart...
 Conclusion
 References
 

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