Why should we consider heart rate in patients with cardiovascular disease?

ANMCO Research Center
Firenze, ITALY
Letizia RIVA,PhD
Department of Cardiology
University Medical Center Groningen, Groningen

Why should we consider heart rate in patients with cardiovascular disease?

by B. D. Westenbrink and W. H. van Gilst , The Netherlands

Heart rate has a fundamental role in cardiovascular performance and is one of the most readily accessible and informative vital signs. An elevated heart rate is an independent risk factor for mortality and morbidity in people with and without cardiovascular disease. Accordingly, pharmacological agents that reduce heart rate can alleviate symptoms and improve clinical outcomes in several cardiac diseases. Unfortunately, perhaps because of our familiarity with heart rate, or the lack of clear data to support a specific heart rate range, heart rate is often overlooked. In this review we will discuss the value of elevated heart rate and its reduction in cardiovascular disease and attempt to provide practical, evidence-based recommendations for its management.

Medicographia. 2012;34:421-425 (see French abstract on page 425)

How to measure heart rate

Heart rate is one of the most readily accessible vital signs. It can be determined in virtually any setting, by any health care provider, and by many patients themselves. In hospitalized patients, heart rate is documented at least daily, with every electrocardiogram, during most medical procedures, and/or continuously. Exercise equipment and commercial blood pressure monitors report heart rate values at home, familiarizing patients with their basic cardiovascular dynamics. Expanding indications for implantable medical devices allow us to remotely monitor heart rates, without even involving the patient. Cardiovascular clinicians are thus continuously informed about their patients’ heart rate. While electrocardiographic detection is the most accurate, palpation of the peripheral pulse may suffice in most instances and most patients. There are, of course, several other aspects of heart rate measurement that should be taken into account, including posture, physical activity, duration of measurement, temperature, and emotional factors, none of which we shall discuss in detail in this paper.

Why should we consider heart rate?

Heart rate has an intimate and complex involvement in several parameters of cardiovascular function and pathophysiology. Cardiac output, for instance, is determined by heart rate and stroke volume. Since it is vastly easier to modulate heart rate than stroke volume, variations in heart rate are our principal mechanism for adjusting cardiac output to metabolic demand. Heart rate is also, however, a major determinant of myocardial oxygen consumption. Sustained elevation in heart rate may lead to critical pathophysiological changes in the cardiovascular system. These include endothelial dysfunction and atherosclerotic plaque development, reduction in coronary blood flow, impaired systolic and diastolic left ventricular function, and a susceptibility to arrhythmia. Higher heart rates predict cardiovascular events and mortality in patients with or without prior cardiovascular disease.1,2

While this association has been known for decades,3 it is still very timely. A subgroup analysis of the placebo arm of the BEAUTIFUL trial (morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction), for instance, demonstrated that a resting heart rate of 70 bpm or higher was a strong and independent predictor of long-term outcome in patients with coronary artery disease.4 In a similar analysis of the SHIFT trial (Systolic Heart failure treatment with the If inhibitor ivabradine Trial) in heart failure patients with a heart rate above 70 bpm despite optimal β-blocker therapy, risk of death in the highest heart rate quintile (>87 bpm) was more than that in the lowest quintile (70-72 bpm).5

Prognostic value is not confined to resting rates. The chronotropic response to exercise and subsequent efficiency of heart rate recovery have also been associated with cardiovascular events and mortality in presence or absence of prior cardiovascular disease.6 The value of the exercise heart rate is extensively discussed in another review in this issue of Medicographia.

Heart rate is not only of prognostic importance, but is also an established therapeutic target. Pharmacological therapies that reduce heart rate are associated with improved coronary perfusion, reduced myocardial oxygen consumption, enhanced left ventricular function, and beneficial left ventricular remodeling.2,7-9 These functional changes translate into improvements in exercise capacity, cardiac function, angina, and quality of life.2,7-9 The beneficial effects of β-blockers on survival are also proportional to the degree of heart rate reduction achieved, suggesting that it is the most important therapeutic target.10 More direct and unequivocal evidence for heart rate reduction is currently emerging from studies with the specific heart rate–reducing agent ivabradine.11 In summary, there is thus ample pathophysiological, epidemiological, and clinical evidence that elevated heart rate has deleterious effects for cardiovascular patients. The evidence that supports heart rate reduction in clinical practice is discussed below.

Which cardiovascular patients might benefit from heart rate reduction?

_ Hypertension
The inverse relation between heart rate and prognosis can be extended to patients with hypertension.12 However, the value of heart rate reduction with β-blockers in patients with hypertension is disputed.13 The CAFE study (Conduit Artery Function Evaluation) compared the effects of atenolol and amlodipine on central and peripheral blood pressure.14 Atenolol was associated with a paradoxical increase in central blood pressure, while the converse was true for amlodipine.14 In addition, an atenolol-based antihypertensive regimen conferred less cardiovascular risk reduction than an amlodipine-based regimen.15 Heart rate reduction is therefore not a specific treatment target in patients with hypertension.12Stable coronary artery disease
Heart rate reduction is an important method of reducing myocardial oxygen consumption in patients with stable coronary artery disease. Heart rate reduction with β-blockers or calcium channel blockers reduces the manifestations of ischemia. Indeed, anti-ischemic drugs that reduce heart rate are often more effective than regimens with no effect on heart rate.9 There is, however, no evidence that heart rate reduction with these conventional agents improves prognosis or reduces the incidence of acute coronary syndromes.9 The benefits of ivabradine on angina are also fairly well established and seem at least proportional to those of β-blockers and calcium channel blockers.16,17 Ivabradine added to an atenolol-based regimen further reduces angina and improves exercise capacity.18 The BEAUTIFUL trial tested whether specific heart rate reduction with ivabradine improves clinical outcomes in patients with stable coronary artery disease and left ventricular systolic dysfunction. Surprisingly, ivabradine did not reduce the incidence of the primary composite end point of mortality, myocardial infarction, or heart failure hospitalization.19 Clear survival benefit was, however, apparent in a prespecified subgroup analysis of patients with a resting heart rate above 70 bpm and in patients with limiting angina. These findings suggest that the lack of benefit in BEAUTIFUL could be explained by a relatively heterogeneous population with a large proportion of patients in whom heart rate was already well controlled. Thus, although three classes of heart rate–modifying drugs alleviate symptoms, unequivocal evidence of mortality benefit is lacking and recommendations for a specific heart rate range cannot be made. It would, however, be prudent to target heart rates to values between 50-70 bpm (see below), although treatment should always focus on symptom alleviation rather than on heart rate values themselves.

_ Acute coronary syndromes
The effect of heart rate on myocardial oxygen consumption is especially critical in acute coronary syndromes. Indeed, an elevated admission heart rate is one of the most important predictors of early mortality.20 Heart rate–lowering anti ischemic drugs can reduce symptoms in patients with acute coronary syndromes.21 Furthermore, several trials and meta analyses have demonstrated that β-blockers reduce mortality and prevent reinfarctions when initiated in the subacute phase after acute myocardial infarction.22 It is, however, unknown whether early heart rate reduction is beneficial in acute coronary syndromes. Indeed, early intravenous β-blockers followed by oral doses during acute ST-segment elevation myocardial infarction (STEMI) was not associated with net clinical benefit, due in part to an increased incidence of cardiogenic shock.23-26 These studies used very high doses of β-blockers and were conducted in the pre-reperfusion era, suggesting that results may have differed if performed with current drugs or titration schemes. The efficacy of early heart rate reduction with ivabradine is currently under investigation in patients with acute coronary syndromes.27 Oral β-blockers are recommended in all patients with acute coronary syndromes and calcium channel blockers in patients who remain symptomatic despite β-blockers and nitrates.8,21 There is no evidence to support specific heart rate targets during acute coronary syndromes. Considering the efficacy of β-blockers after myocardial infarction and the results of the SHIFT study (see below), targeting a heart rate range between 50 to 70 bpm appears sensible.

_ Heart failure
Myocardial workload and oxygen consumption are directly proportional to heart rate, while diastolic filling time and oxygen delivery are inversely related to heart rate. Elevated heart rates are especially detrimental to the failing heart, which relies heavily on diastolic filling and is relatively deprived of oxygen and nutrients. Accordingly, heart rate reduction in failing hearts is associated with decreased energy expenditure, improved perfusion, improved contractility, decreased afterload, and restoration of ventricular synchrony.1,2,5,28 The first evidence that heart rate reduction could enhance clinical outcome was presented in the DIG trial (Digitalis Investigation Group).29 Heart rate reduction with digoxin reduced hospital admission for worsening heart failure, although it did not reduce mortality. More robust evidence for heart rate reduction came from multiple randomized controlled trials that firmly established the efficacy of β-blockers in heart failure.7 Importantly, the mortality benefits of β-blockers are strongly related to the degree of heart rate reduction achieved.10 β-Blockers and digoxin have several cardiovascular and extra cardiovascular (side) effects that may partially explain their efficacy, but also affect their tolerability. Indeed, only 56% of patients tolerated the target dose of carvedilol in the COPERNICUS trial (CarvedilOl ProspEctive RaNdomIzed CUmulative Survival),30 and even fewer patients tolerate the target dose of β-blockers outside the clinical trial setting.31 While individual dose-response characteristics vary and careful titration may allow patients to tolerate higher doses,32 side effects significantly limit the degree of heart rate reduction that can be achieved. The SHIFT study specifically targeted those patients with heart rate control that remained suboptimal on conventional medication.11 In SHIFT, 6505 chronic systolic heart failure patients in sinus rhythm with a resting heart rate ≥70 bpm despite a maximally tolerated β-blocker dose were randomized to ivabradine or placebo. Ivabradine was titrated to a target dose rather than a heart rate target, but the dose was reduced when heart rate dropped below 50 bpm. It achieved an average heart rate reduction of 11 bpm and reduced the occurrence of the primary composite end point of cardiovascular death or heart failure hospitalizations by 18%. This effect was mainly driven by a 26% reduction in hospitalizations for worsening heart failure or heart failure-related deaths. Prespecified post-hoc analysis also showed that heart rate reduction reversed left ventricular remodeling and improved both cardiac function and quality of life.33,34 This study not only shows ivabradine to be effective, but also unequivocally proves that heart rate is a nodal point for intervention in the cardiovascular system.

Which rate is best for the heart?

Extensive epidemiological studies and the evidence provided by the BEAUTIFUL and SHIFT trials indicate that heart rates above 70 bpm are unfavorable. More importantly, they show that reducing heart rate in these patients can improve clinical outcome. Although the SHIFT and the BEAUTIFUL studies did not target a specific heart rate range, the dose was adjusted when the heart rate fell below 50 bpm. We therefore propose that the optimal resting heart rate range is between 50 and 70 bpm, at least in patients with heart failure, stable coronary artery disease, and left ventricular systolic dysfunction. However, the inclusion criteria for these studies were broadly defined and not mutually exclusive. The primary etiology for left ventricular dysfunction and heart failure, for instance, is a previous acute coronary syndrome. It is therefore likely that the findings of both trials can be extrapolated to other populations as well. The optimal heart rate range for patients with heart disease is probably between 50 to 70 bpm. Future studies with ivabradine will hopefully help us to further define the optimal heart rate targets. Moreover, new avenues for heart rate reduction will likely emerge.35


Extensive data from pathophysiological and epidemiological studies and clinical trials have established heart rate reduction as an effective and feasible tool to alleviate symptoms and improve prognosis in patients with coronary artery disease and heart failure. Trials with the specific heart rate–reducing agent ivabradine have unequivocally proven this concept and provided us with a novel and specific tool to control heart rate. _


1. Custodis F, Schirmer SH, Baumhakel M, Heusch G, Böhm M, Laufs U. Vascular pathophysiology in response to increased heart rate. J Am Coll Cardiol. 2010;56:1973-1983.
2. Fox KM, Ferrari R. Heart rate: A forgotten link in coronary artery disease? Nat Rev Cardiol. 2011;8:369-379.
3. Kannel WB, Kannel C, Paffenbarger RS Jr, Cupples LA. Heart rate and cardiovascular mortality: The Framingham study. Am Heart J. 1987;113:1489-1494.
4. Fox K, Ford I, Steg PG, Tendera M, Robertson M, Ferrari R. Heart rate as a prognostic risk factor in patients with coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): A subgroup analysis of a randomised controlled trial. Lancet. 2008;372:817-821.
5. Böhm M, Swedberg K, Komajda M, et al. Heart rate as a risk factor in chronic heart failure (SHIFT): The association between heart rate and outcomes in a randomised placebo-controlled trial. Lancet. 2010;376:886-894.
6. Palatini P, Grassi G. Assessment of exercise blood pressure and heart rate in patients with coronary artery disease: Is it worth it? J Hypertens. 2010;28:2184- 2187.
7. Dickstein K, Cohen-Solal A, Filippatos G, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM). Eur Heart J. 2008;29:2388-2442.
8. Hamm CW, Bassand JP, Agewall S, et al. ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: The Task Force for the Management of Acute Coronary Syndromes (ACS) in Patients presenting Without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC). Eur Heart J. 2011;32:2999-3054.
9. Skalidis EI, Vardas PE. Guidelines on the management of stable angina pectoris. Eur Heart J. 2006;27:2606; author reply 2606-2607.
10. Flannery G, Gehrig-Mills R, Billah B, Krum H. Analysis of randomized controlled trials on the effect of magnitude of heart rate reduction on clinical outcomes in patients with systolic chronic heart failure receiving beta-blockers. Am J Cardiol. 2008;101:865-869.
11. Swedberg K, Komajda M, Böhm M, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): A randomised placebo-controlled study. Lancet. 2010; 376:875-885.
12. Palatini P, Benetos A, Grassi G, et al. Identification and management of the hypertensive patient with elevated heart rate: Statement of a European Society of Hypertension Consensus Meeting. J Hypertens. 2006;24:603-610.
13. Palatini P. Elevated heart rate in hypertension: A target for treatment? J Am Coll Cardiol. 2010;55:931; author reply 931-932.
14. Williams B, Lacy PS, Thom SM, et al. Differential impact of blood pressurelowering drugs on central aortic pressure and clinical outcomes: Principal results of the Conduit Artery Function Evaluation (CAFE) study. Circulation. 2006; 113:1213-1225.
15. Poulter NR, Wedel H, Dahlof B, et al. Role of blood pressure and other variables in the differential cardiovascular event rates noted in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA). Lancet. 2005;366:907-913.
16. Ruzyllo W, Tendera M, Ford I, Fox KM. Antianginal efficacy and safety of ivabradine compared with amlodipine in patients with stable effort angina pectoris: A 3-month randomised, double-blind, multicentre, noninferiority trial. Drugs. 2007;67:393-405.
17. Tardif JC, Ford I, Tendera M, Bourassa MG, Fox K. Efficacy of ivabradine, a new selective I(f) inhibitor, compared with atenolol in patients with chronic stable angina. Eur Heart J. 2005;26:2529-2536.
18. Tardif JC, Ponikowski P, Kahan T. Efficacy of the I(f) current inhibitor ivabradine in patients with chronic stable angina receiving beta-blocker therapy: A 4- month, randomized, placebo-controlled trial. Eur Heart J. 2009;30:540-548.
19. Fox K, Ford I, Steg PG, Tendera M, Ferrari R. Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): A randomised, double-blind, placebo-controlled trial. Lancet. 2008;372:807- 816.
20. Lee KL, Woodlief LH, Topol EJ, et al. Predictors of 30-day mortality in the era of reperfusion for acute myocardial infarction. Results from an international trial of 41,021 patients. GUSTO-I investigators. Circulation. 1995;91:1659-1668.
21. Van de Werf F, Bax J, Betriu A, et al. Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation: The Task Force on the Management of ST-Segment Elevation Acute Myocardial Infarction of the European Society of Cardiology. Eur Heart J. 2008;29:2909-2945.
22. Freemantle N, Cleland J, Young P, Mason J, Harrison J. Beta blockade after myocardial infarction: Systematic review and meta regression analysis. BMJ. 1999;318:1730-1737.
23. Chen ZM, Pan HC, Chen YP, et al. Early intravenous then oral metoprolol in 45,852 patients with acute myocardial infarction: Randomised placebo-controlled trial. Lancet. 2005;366:1622-1632.
24. Hjalmarson A, Herlitz J, Holmberg S, et al. The Göteborg metoprolol trial. Effects on mortality and morbidity in acute myocardial infarction. Circulation. 1983; 67:I26-I32.
25. Metoprolol in Acute Myocardial Infarction (MIAMI). A randomised placebo-controlled international trial. The MIAMI trial research group. Eur Heart J. 1985;6: 199-226.
26. Randomised trial of intravenous atenolol among 16 027 cases of suspected acute myocardial infarction: ISIS-1. First International Study of Infarct Survival Collaborative Group. Lancet. 1986;2:57-66.
27. Fasullo S, Cannizzaro S, Maringhini G, et al. Comparison of ivabradine versus metoprolol in early phases of reperfused anterior myocardial infarction with impaired left ventricular function: preliminary findings. J Card Fail. 2009;15:856- 863.
28. Reil JC, Reil GH, Böhm M. Heart rate reduction by I(f)-channel inhibition and its potential role in heart failure with reduced and preserved ejection fraction. Trends Cardiovasc Med. 2009;19:152-157.
29. Ahmed A, Rich MW, Love TE, et al. Digoxin and reduction in mortality and hospitalization in heart failure: A comprehensive post hoc analysis of the DIG trial. Eur Heart J. 2006;27:178-186.
30. Maggioni AP, Dahlstrom U, Filippatos G, et al. EURObservational research programme: The Heart Failure Pilot Survey (ESC-HF Pilot). Eur J Heart Fail. 2010; 12:1076-1084.
31. Packer M, Fowler MB, Roecker EB, et al. Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study. Circulation. 2002; 106:2194-2199.
32. Cullington D, Goode KM, Cleland JG, Clark AL. Limited role for ivabradine in the treatment of chronic heart failure. Heart. 2011;97:1961-1966.
33. Ekman I, Chassany O, Komajda M, et al. Heart rate reduction with ivabradine and health related quality of life in patients with chronic heart failure: Results from the SHIFT study. Eur Heart J. 2011;32:2395-2404.
34. Tardif JC, O’Meara E, Komajda M, et al. Effects of selective heart rate reduction with ivabradine on left ventricular remodelling and function: Results from the SHIFT echocardiography substudy. Eur Heart J. 2011;32:2507-2515.
35. Nuding S, Ebelt H, Hoke RS, et al. Reducing elevated heart rate in patients with multiple organ dysfunction syndrome by the I(f) (funny channel current) inhibitor ivabradine: Modi(f)y trial. Clin Res Cardiol. 2011;100:915-923.

Keywords: coronary artery disease; heart failure; heart rate; heart rate reduction; hypertension; ivabradine