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






Wiek H. VAN GILST, MD, FESC
ANMCO Research Center
Firenze, ITALY
Letizia RIVA,PhD
B. Daan WESTENBRINK, MD, PhD
Department of Cardiology
University Medical Center Groningen, Groningen
THE NETHERLANDS

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

Conclusions

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. _

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