How to optimize anti-ischemic therapy in patients undergoing cardiac rehabilitation

by S. Marazia, M. Contini,
V. M. Parato, and M. Di Mauro, Italy

aStefania MARAZIA, MD
cVito Maurizio PARATO, MD
dMichele DI MAURO, MD
aCardiology Unit and EchoLab
Emergency Department,
« V. Fazzi » Hospital, Lecce, ITALY
bDepartment of Cardiovascular
Surgery, Villa Verde Clinic
Taranto, ITALY
cCardiology Unit and EchoLab
Emergency Department
Madonna del Soccorso
Hospital, Marche Politechnic
University, San Benedetto del
Tronto, ITALY
dDepartment of Cardiovascular
Disease, University of L’Aquila
L’Aquila, ITALY

Cardiac rehabilitation programs present an opportunity to improve the functional status of patients and help them to reach and maintain optimal physical, psychological, and social functional levels. Optimal pharmacological therapy, which improves coronary perfusion, symptoms, exercise capacity, and quality of life, is not only an essential part of patient management, but also acts in synergy with cardiac rehabilitation to achieve the goals of patient management. Heart rate is not just a physical sign; it is a biomarker and a therapeutic target in patients with cardiovascular disease. It regulates myocardial oxygen consumption and coronary flow, and plays a central role in adapting the cardiac output to the metabolic needs of the whole body. In many cardiac diseases, an increase in heart rate is associated with a higher mortality. Ivabradine is a pure heart rate–reducing agent with anti-ischemic and anti-anginal effects but without any influence on blood pressure and contractility, and it is therefore well tolerated. Since heart rate determines oxygen consumption and delivery, its modulation by ivabradine strongly influences cardiac performance and exercise tolerance and leads to functional status improvement in all patients taking part in cardiac rehabilitation programs.

Cardiac rehabilitation—after a diagnosis of coronary artery disease (CAD), heart failure, and heart surgery—has gradually evolved over the past two decades from exercise-based interventions to comprehensive, professional, lifestyle programs that include smoking cessation, diet modification, control of cardiovascular risk factors, and behavioral interventions. Patients who undergo percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) after an acute coronary syndrome and patients with heart failure have a high prevalence of modifiable risk factors, so the primary aim of cardiac rehabilitation programs should be lifestyle modification and optimization of medical therapy. Functional capacity improvement should be a priority of cardiac rehabilitation programs, as it is directly related to quality of life.

Heart rate is a major determinant of myocardial oxygen demand, coronary blood flow, myocardial performance, and functional capacity in the general population1,2 and in patients with cardiovascular disease.3 In various heart conditions, increased heart rate, especially overnight, is associated with a higher mortality. The crucial role of heart rate is highlighted by the fact that maximal heart rate during exercise and heart rate recovery are the most commonly used parameters in cardiology for assessing the effects of rehabilitation and exercise training. Rate-adaptive cardiac pacing was developed to optimize exercise tolerance in patients with chronotropic incompetence, structural heart disease, or both acting in concert. A sustained increase in heart rate by atrial or ventricular pacing in animal models induces left ventricular dysfunction along with symptoms of heart failure (dyspnea, cachexia, congestion, and exercise intolerance).4-12

Although cardiac rehabilitation programs are of great importance for all patients with heart disease, research in this area has mainly focused on patients with recent myocardial infarction or undergoing myocardial revascularization. In recent years, however, a growing number of studies have been conducted in other groups of patients, especially older patients, women, and patients at higher risk of heart failure or angina. In this paper we analyze the effect of heart rate in patients undergoing cardiac rehabilitation and the role of ivabradine in this setting.

Patients with stable coronary artery disease

Improved survival, coupled with a decline in the incidence of acute myocardial infarctions, has dramatically changed the pattern of health care use over recent years. Patients with stable CAD have somehow “fallen off the radar” of clinical interest: no longer in cardiac rehabilitation (which is mainly offered immediately after acute myocardial infarction or CABG), discharged from ongoing specialist care, and with suboptimal drug compliance, adherence, and persistence. These patients, however, vary widely in their risk of subsequent acute myocardial infarction or coronary death—there is approximately a 10-fold difference between the top and bottom deciles of risk—and this clearly has different resource implications.

Increased heart rate results in increased myocardial oxygen consumption,13-15 and reduced diastolic function.16 When the coronary circulation is free from occlusion, metabolic vasodilation can compensate for decreased diastolic duration and adjust to the increased oxygen demand with increased oxygen supply.16,17 However, in the presence of atherosclerotic narrowing/ stenosis of an epicardial coronary artery and coronary microvascular dysfunction, the scenario is very different. Increased heart rate can exacerbate hemodynamic impairment caused by coronary stenosis. In such cases, vasodilation can maintain normal coronary blood flow at rest; but it is unable to respond to further increases in heart rate during stress.17 The decrease in diastolic duration now even reduces coronary blood flow, which particularly affects the more vulnerable subendocardial layers of the myocardium.18,19 In this scenario, collateral blood flow from the adjacent myocardium is also reduced with increased heart rate because the driving pressure gradient for collateral blood flow is reduced. Pressure at the orifice of collaterals into the post-stenotic coronary circulation is increased since the post-stenotic coronary vascular bed is already maximally dilated to compensate for the stenosis, and decreased diastolic duration then reduces coronary blood flow or, conversely, increases coronary resistance.20

Ivabradine-mediated heart rate reduction reverses the unfavorable blood flow to the ischemic myocardium.21 In contrast to β-blockade, which also reduces heart rate and improves blood flow to the ischemic myocardium,22 ivabradine has no negative inotropic effect and does not unmask α-adrenergic coronary vasoconstriction23-26 during sympathetic activation, eg, by exercise.27 There is an ongoing debate regarding the effects of β-blockade and the unmasking of α-adrenergic coronary vasoconstriction. β-Blockade reduces oxygen consumption in non-ischemic myocardium more than ivabradine for an equivalent reduction in heart rate.28 As long as heart rate is reduced, β-blockade also induces a favorable redistribution of blood flow toward the ischemic myocardium during sympathetic activation29,30 but, in the absence of heart rate reduction, β-blockade reduces regional myocardial blood flow and contractile function in exercise-induced myocardial ischemia.31 α-Adrenergic coronary vasoconstriction during sympathetic activation has been proposed to maintain a uniform transmural blood flow distribution,32,33 or to cause a more favorable blood flow distribution toward the ischemic myocardium,34 but both these hypotheses are contentious.24 All available clinical studies suggest a deleterious role for α-adrenergic coronary vasoconstriction in myocardial ischemia26,35-39; therefore, the fact that ivabradine is not associated with α-adrenergic coronary vasoconstriction is an advantage.

Several small proof-of-concept trials have demonstrated the symptomatic efficacy of ivabradine in reducing anginal pain and improving exercise tolerance.40-44 In the large BEAUTIFUL trial (morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction) in patients with stable CAD and left ventricular systolic dysfunction, ivabradine reduced hospitalization for myocardial infarction and coronary revascularization, particularly in patients with angina and a resting heart rate >70 bpm at baseline.45 The reductions in these endpoints (75% reduction in hospitalization for myocardial infarction and 59% reduction in coronary revascularizations) appeared largely out of proportion with the small (7 bpm) placebo-corrected heart rate reduction.46 More recently, in the large SIGNIFY study (Study assessInG the morbidity-mortality beNefits of the If inhibitor ivabradine in patients with coronarY artery disease) in patients with stable CAD with preserved ejection fraction, ivabradine did not reduce the primary composite end point of death from cardiovascular causes or nonfatal myocardial infarction.47 Heart rate reduction with ivabradine improves symptoms, but not clinical outcome in patients with stable CAD and preserved ejection fraction; this is also true for all other antianginal drugs on the market and for β-blockers too.

Patients after myocardial infarction

During ischemia—and in particular if the heart rate is elevated— the ventricular muscle develops diastolic dysfunction. The resulting rise in filling pressure impairs exercise tolerance and increases pulmonary wedge pressure, causing shortness of breath. Ivabradine has previously been shown to reduce heart rate after myocardial stunning, and also after PCI for ST-segment elevation myocardial infarction (STEMI).48 In the VIVIFY study (eValuation of the IntraVenous If inhibitor ivabradine after ST-segment elevation mYocardial infarction), the use of intravenous ivabradine in STEMI patients produced a rapid and sustained reduction in heart rate, which was safe and well tolerated and did not affect blood pressure or hemodynamic parameters.48 Furthermore, in STEMI patients treated with primary PCI, heart rate at discharge correlates with mortality.49 In the failing heart, the Bowditch effect is impaired, resulting in a negative force-frequency relationship in vitro and in vivo. Initial evidence to this effect came from isolated cardiac preparations from patients undergoing heart transplantation.50 Failing heart preparations also develop a relaxation deficit at higher heart rates.50 In patients after a Q-wave myocardial infarction with early left ventricular ejection fraction (LVEF) <45%, combining ivabradine to low-dose metoprolol tartrate was associated with improved systolic and diastolic left ventricular function, decreased serum NT-pro-ANP by day 25,51 and increased exercise tolerance at the 6-month follow-up, compared with uptitrating the metoprolol dose.52

Ivabradine is a pure heart rate–reducing agent that has no effect on blood pressure and contractility and can reverse left ventricular (LV) remodeling in patients with heart failure.53 Since heart rate determines oxygen consumption and delivery, its modulation by ivabradine strongly influences exercise tolerance, in particular during ischemia. This property makes ivabradine a valuable component in the armamentarium of coronary therapy even in the early phase of myocardial infarction, with long-term benefits in terms of cardiac performance and functional capacity.

The stepwise process of rehabilitation begins immediately after a cardiac event and continues throughout life, with different interventions introduced at appropriate stages. Standard drug therapy for post-infarct patients is usually instituted while patients are still in hospital. After being able to sit up, patients may walk in the corridors for 2 to 5 minutes, 4 times daily. Their heart rate should not exceed 120 bpm, and in patients with resting tachycardia it should not be greater than 20 bpm above the resting heart rate.

Exercise stress testing and ECG is required in high-risk patients to assess ventricular function and residual ischemia and for those who wish to participate in high-intensity exercise. High-risk patients (patients with residual ischemia or significant left ventricular dysfunction) require constant monitoring and their heart rate should not be allowed to exceed 10 bpm below the rate at which ischemia was provoked on stress testing. Impaired chronotropic response (failure to reach 80% of maximum heart rate) is associated with increased mortality post–myocardial infarction, especially with heart failure, and may be improved by β-blockade and ivabradine. The combination of ivabradine with low-dose bisoprolol in stable angina patients produces more antianginal and anti-ischemic benefits than twice the dose of the β-blocker alone and also improves chronotropic reserve.54

Figure 1. Diastolic function at admission, discharge, and at the
3-month follow-up of coronary artery bypass graft (CABG) patients
randomized to either standard medical therapy including bisoprolol
2.5 mg to 3.75 mg once daily (BB) or ivabradine 5 mg twice a day
+ standard medical therapy including bisoprolol 1.25 mg once
daily (I-BB).
Based on data from reference 57: Marazia et al. J Cardiovasc Pharmacol Ther.

Figure 2. Systolic function at admission, discharge, and at the 3-
month follow-up of coronary artery bypass graft (CABG) patients
randomized to either standard medical therapy including bisoprolol
2.5 mg to 3.75 mg once daily (BB group, blue line) or ivabradine
5 mg twice a day + standard medical therapy including bisoprolol
1.25 mg once daily (I-BB group, red line).*P<0.05.
Based on data from reference 57: Marazia et al. J Cardiovasc Pharmacol Ther.

Patients with recent coronary artery bypass graft or percutaneous transluminal coronary angioplasty

The European Society of Cardiology (ESC) guidelines for myocardial revascularization recommend adequate medical therapy, other secondary prevention strategies for risk factor modification, and permanent lifestyle changes as goals to achieve after myocardial revascularization.55 Cardiac rehabilitation is an integral part of the management strategy after revascularization, because such measures reduce future morbidity and mortality in a cost-effective way and can further ameliorate symptoms. In this sense, even though not clearly specified in the guidelines, heart rate control might have an added value in revascularized patients, even in the presence of normal ejection fraction. β-Blockers are especially useful in patients with previous acute myocardial infarction or heart failure. Although the 2011 American College of Cardiology Foundation/American Heart Association (ACCF/AHA) Guidelines for CABG recommend that β-blockers should be prescribed to all CABG patients without contraindications at the time of hospital discharge, 56 the number of CABG patients discharged from heart surgery with β-blockers ranges between 67.4% and 83%.57

Adding ivabradine to low-dose bisoprolol (1.25 mg once daily) in patients undergoing cardiac rehabilitation after recent CABG surgery has been shown to provide further benefits compared with standard medical therapy (including bisoprolol 2.5 mg to 3.75 mg once daily). Taking the ivabradine/ bisoprolol regimen shortly after CABG was associated with improved functional status, enhanced diastolic function (Figure 1), and increased LVEF (Figure 2), with no negative cardiovascular effects. In addition, adding ivabradine to standard therapy including bisoprolol can improve exercise capacity (Figures 3 and 4).57

Cardiac surgery and cardiopulmonary bypass trigger inflammation and apoptosis. Transient myocardial ischemia and the ischemia-reperfusion phenomenon lead to myocardial stunning. There are two main determinants of this phenomenon: local production of free oxygen radicals and altered myocyte calcium homeostasis. Inflammatory response, operative trauma, myocardioplegia and priming volume, and nonpulsatile flow during cardiopulmonary bypass may impair systolic and diastolic function in the postoperative period. Optimization of hemodynamic parameters (ie, heart rate, ventricular filling pressure, and mean arterial pressure) is crucial in the postoperative phase. β-Blockers have well-documented direct effects on cardiovascular and pulmonary function, causing symptoms such as fatigue and dizziness.58 Because of these effects and other adverse effects—hypotension, dyspnea, cardiac decompensation, and excessive bradycardia—target doses of β-blockers may be difficult to achieve. Adverse effects like fatigue and dyspnea may also explain why β-blockers have been shown to limit exercise capacity in healthy individuals.59 Ivabradine could play a crucial role in the setting of cardiac rehabilitation, as it is devoid of inotropic, lusitropic, or vasoactive effects. Since ivabradine and β-blockers use distinct mechanisms of action to reduce heart rate, the combination of ivabradine with low-dose bisoprolol appears to be a valuable option in patients with CABG undergoing cardiac rehabilitation.60

Figure 3. Distance covered by coronary artery bypass graft (CABG)
patients randomized to either standard medical therapy including
bisoprolol 2.5 mg to 3.75 mg once daily (BB group, light gray
columns) or to ivabradine 5 mg twice a day + standard medical
therapy including bisoprolol 1.25 mg once daily (I-BB group, dark
gray columns) during the 6-minute walking test at admission, discharge,
and 3-month follow-up. *P<0.05 (between BB and I-BB).
Standard deviation is plotted. The increases in median distance
covered from admission to discharge, from discharge to follow-up,
and from admission to follow-up are shown under the graph
(ranges shown in brackets).
Reproduced from reference 57: Marazia et al. J Cardiovasc Pharmacol Ther.
2015;20:547-553. © 2015, The Author(s).

Figure 4. Heart rate at each minute of the 6-minute walking test
at admission, discharge, and follow-up of patients with coronary
artery bypass graft (CABG) randomized to either standard medical
therapy including bisoprolol 2.5 mg to 3.75 mg once daily
(BB group; light gray diamonds, solid lines) or to ivabradine 5 mg
twice a day + standard medical therapy including bisoprolol
1.25 mg once daily (I-BB group; dark gray squares, dotted lines).
Reproduced from reference 57: Marazia et al. J Cardiovasc Pharmacol Ther.
2015;20:547-553. © 2015, The Author(s).

In a recent multicenter survey, cardiac rehabilitation was found to increase patient adherence to β-blockers from 67.4% to 88.8% at discharge.61 In patients admitted for cardiac rehabilitation after myocardial revascularization, heart rate lowering is a useful objective, even if in most cases the target dose of β-blocker is not easily achievable because these patients are highly susceptible to hypotension, mainly because of unstable hemodynamic conditions and the use of diuretic therapy to reduce fluid retention following cardiopulmonary bypass. Moreover, in the months following the procedure, heart rate variability increases due to a transient loss of autonomic control, so these patients tend to alternate between tachycardia and bradycardia. Here, the use of a higher dose of β-blocker may be dangerous, whereas ivabradine, whose effect on If channels is frequency-dependent, carries a lower risk of bradycardia.

The results of the SHIFT trial (Systolic Heart failure treatment with the If inhibitor ivabradine Trial) showed that a decrease in heart rate with ivabradine reversed LV remodeling in patients with heart failure.8 Similarly, ivabradine improved the LV pressure- volume relationship, decreased interstitial collagen content, and increased capillary density in young adult rats with acute myocardial infarction and congestive heart failure.62 Only one trial investigated the effects of ivabradine versus β-blockers using echocardiography in patients with anterior STEMI and impaired LV function treated with primary PCI.63 In this study, at the 2-month follow-up, patients treated with ivabradine had a significant increase in LVEF, with a concomitant reduction in LV end-systolic volume (LVESV) and LV end diastolic volume (LVEDV) compared with the metoprolol group. However, in this randomized trial, patients in the ivabradine group were not given β-blockers and ivabradine was delivered late after angioplasty (ie, 12 hours).

A pilot study has evaluated the additional value of ivabradine in STEMI patients treated with successful primary PCI (TIMI 3 reperfused STEMI) and optimal medical therapy. Early administration of ivabradine was shown to improve LV remodeling when added to current guideline-based therapy, including β-blockers (Figure 1). Clinical and experimental studies have revealed several mechanisms that may explain the beneficial effects of ivabradine on cardiac remodeling. First, ivabradine does not have negative inotropic or lusitropic effects; so hemodynamic and myocardial contractility are not impaired.64,65 Ivabradine leads to a decrease in heart rate, which reduces myocardial oxygen demand and simultaneously improves oxygen supply by prolonging diastole, which allows increased coronary flow and myocardial oxygenation. Second, Mulder et al showed that ivabradine improves the LV pressure-volume relationship, prevents LV systolic dysfunction, and increases capillary density in a rat model of congestive heart failure.62 Similarly, Dedkov et al have documented several effects of ivabradine in middle-aged rats with acute myocardial infarction, including reduction of periarterial and interstitial collagen content, attenuation of the increase in end-diastolic pressure, and attenuation of the decrease in LVEF./sup>66 These beneficial effects of ivabradine after acute myocardial infarction were investigated in models of permanent coronary ligation. Third, in a rabbit model of ischemia reperfusion, Couvreur et al observed that ivabradine reduces myocardial stunning in rats with acute myocardial infarction and congestive heart failure.67

Elderly patients

Following hospitalization for a coronary event such as an acute coronary syndrome or heart failure, all patients—and in particular the elderly—are at increased risk of disability, including a repeat cardiovascular event. Nowadays, patients with stable CAD, including patients with stable angina and those who have become stable after an acute coronary syndrome, are older and living longer, and so make greater use of health care resources. Despite their poor prognosis and high hospital admission rate, the management of this population is often suboptimal. Effective drugs are underprescribed and interventions that improve patient outcomes such as education, psychosocial counseling, and lifestyle modification, are not widely available yet. Despite the increasing prevalence of CAD among older patients, there seems to be a strong age bias in the treatment of cardiovascular diseases, including preventive strategies.

Although elderly patients are often underrepresented in clinical trials, they are perhaps most likely to benefit from a multidisciplinary approach because of polypharmacy, comorbidity, and poor health-related quality of life. Therefore, cardiac rehabilitation is an effective model of care for older patients.68 Cardiac rehabilitation programs are designed to enhance recovery from acute cardiovascular events and to improve both quality of life and survival. In addition, patients with stable coronary heart disease treated medically or those who have undergone myocardial revascularization with PCI or CABG surgery derive benefit. The indications for cardiac rehabilitation in the elderly are the same as for the general population.69 Cardiac rehabilitation also results in statistically significant improvements in behavioral characteristics such as scores of anxiety, somatization, depression, and hostility in very elderly patients. The altered functional status of elderly cardiac patients reflects both the anatomical and physiological cardiovascular changes that occur with aging and the dysfunction that results from specific cardiovascular disorders. The changes of aging decrease the reserve capacity of the heart; problems become evident at times of cardiovascular stress, as occurs with disease. Furthermore, cardiac disease in the elderly rarely occurs in isolation; there are typically additive impairments of multiple systemic illnesses that may directly or indirectly impair cardiovascular performance.

The decreases in maximal oxygen consumption, maximal exercise heart rate, exercise stroke volume, and cardiac output that are associated with aging reduce the capacity to exercise, to work, and to tolerate a variety of stresses. Recent studies suggest that cardiac output can be preserved thanks to an increase in stroke volume enabled by an increase in end-diastolic volume. In elderly patients with CAD and other comorbidities, addition of ivabradine reduces heart rate, increases end-diastolic volume, and improves symptoms without modifying the main hemodynamic (noninvasively measured cardiac output, stroke volume, and cardiac index) and echocardiographic (left ventricular ejection fraction and aortic transvalvular gradients) parameters.70


In recent years, there has been impressive progress in pharmacological therapies and sophisticated, technology-based diagnostic and therapeutic procedures in cardiovascular diseases. As a consequence, a greater number of men and women now survive acute events, but with a heavier subsequent burden of chronic conditions and clinical need. Cardiac rehabilitation has been shown to accelerate physical and psychological recovery and reduce mortality after acute cardiac events. Heart rate control improves symptoms, exercise capacity, and quality of life in patients undergoing cardiac rehabilitation programs and provides long-term benefits. In the hospital phase, optimizing β-blocker treatment may not be easy, as hemodynamic conditions are usually unstable. Adding ivabradine early in this context is a possible and promising therapeutic strategy that will need to be validated by specific studies.■

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Keywords: cardiac rehabilitation; coronary artery disease; functional status; myocardial revascularization