Effects of Ivabradine on Residual Myocardial Ischemia After PCI Evaluated by Stress Echocardiography
Phase: PHASE4
Conditions: Angina Pectoris, Stable
Sponsor: Azienda Policlinico Umberto I

Effects of Ivabradine on residual myocardial ischemia after PCI evaluated by 
stress echocardiography. 
 
Protocol Version 2.1  
Date 15/09/2015 
NCT number: not available 
Investigators: Simone Calcagno, MD*, Fabio Infusino, MD*, Olga Dettori, MD*, Temistocle 
Taccheri, MD*, Pasqualina Bruno, MD*, Viviana Maestrini, MD*, Gennaro Sardella, MD*, 
Massimo Mancone, MD PhD* and Francesco Fedele, MD*. 
 
*Cardiovascular, Respiratory, Geriatric, Anesthesiologic and Nephrologic Sciences Department, 
Umberto I Hospital, Sapienza University of Rome, Italy.  
 
INTRODUCTION 
Stable angina is a syndrome characterized by a transitory condition of acute myocardial ischemic 
attacks caused by an imbalance between myocardial perfusion and metabolic demand [1]. The 
antianginal drugs and the percutaneous coronary revascularization, are essential to treat the 
persistent symptoms. However, in some cases, when small vessels or side branches are significantly 
involved with hard or impossible reperfusion, drug therapy is the only strategy to prevent the 
worsening of ischemic heart disease and to reduce the symptoms. Heart rate is the major 
determinant of cardiac output and myocardial oxygen consumption, therefore the reduction of heart 
rate in patients with stable angina can be considered a goal of the therapy [2]. Ivabradine is an 
antianginal agent that specifically inhibits the pacemaker (If) current, resulting in selective HR 
reduction with no negative effects on blood pressure and inotropism [3]. In patients with chronic 
heart failure, Ivabradine improves clinical outcomes if used with beta-blockers under well 
documented efficacy and safety [4]. 

In previous studies, Ivabradine reduced anginal symptomatology but has not clearly demonstrated    
improvements of the outcomes in patients with chronic ischemic disease without left-ventricular 
systolic dysfunction [5-7]. More recently, in CONTROL-2 Study, in patients with stable angina, the 
combination of the two therapies ivabradine and β-blockers together demonstrated good tolerability, 
safety, and also pronounced clinical improvements, compared to β-blockers up titration [8]. 
Moreover, an interesting SHIFT substudy showed the reversed LV remodeling with marked 
reductions of LV volumes and significant improvements of LV ejection fraction (LVEF) in patients 
treated with Ivabradine [9]. 
In this context, in order to define the role of Ivabradine in patients with residual angina after PCI, 
we aimed to quantify the clinical benefits of adding ivabradine to standard antischemic therapy, in 
symptomatic patients for residual myocardial ischemia after PCI, using more precise indicators of 
oxygen consumption. 
Furthermore, we studied the effects of ivabradine on diastolic function (both at rest and after 
exercise) and on the ventricular remodeling.                                                                                                             
 
METHODS. 
We investigated the efficacy of treatments with Ivabradine in addition to full anti-ischemic therapy 
(as per guidelines) compared with the latter alone in patients with signs or symptoms of residual 
angina underwent percutaneous coronary intervention plus stent implantation. The main purpose 
was to evaluate if addition of ivabradine to standard therapy might increase the threshold for angina 
improving the stress tolerance and exercise duration in terms of double product (DP) and triple 
product (TP), respectively calculated as a product between HR and systolic blood pressure and the 
product between DP and ejection time. In our opinion these, indirectly, reflect the true myocardial 
oxygen consumption (MVO2) and the improvement of mechanical load that the ventricle can 
withstand at different levels of exercise. Triple product is closely related to the tension-time index, a 
measure of ventricular work and oxygen demand that is found by multiplying the average pressure 
in the ventricle during the period in which it ejects blood by the time it takes to do this [10]. 

The second objective was to evaluate changes at rest and after the stress test of diastolic function 
and ventricular remodeling, using echocardiographic parameters. 
 
Study Population 
In this randomized, prospective, single-center study, all the patients selected were with chronic 
coronary artery disease undergoing percutaneous coronary intervention (PCI) plus stent 
implantation, residual angina and on treatment with full anti-ischemic therapy with and without 
Ivabradine. In all patients, revascularization was complete as far as possible, all coronary lesions 
resulting in a stenosis greater than 50% in vessels of a caliber greater than two millimeters were 
treated. The inclusion criteria was: coronary artery disease with chronic stable angina for more than 
three months (Canadian Cardiovascular Society–CCS-class I-III); percutaneous revascularization 
with stent implantation at least one; signs/symptoms of residual ischemia; sinus rhythm; HR ≥ 70 
bpm at rest; ability to perform an echocardiogram stress test with the tilting bicycle stress test 
(BST); good acoustic window; age ≥ 18 years. The main exclusion criteria were: drugs intolerance 
or hypersensitivity, EF ≤ 40 % with NYHA class III to IV; CCS IV; atrial fibrillation or flutter; 
presence of a pacemaker or implantable defibrillator; II or III degree AV block; HR ≤ 70 bpm at rest 
or sick sinus syndrome; any condition that could interfere with the ability to exercise stress test like 
Wolff- Parkinson-White syndrome, left bundle branch block, left ventricular hypertrophy; rate-
corrected QT interval (QTc) greater than 500 ms or the use of drugs that prolong the QTc interval; 
symptomatic hypotension or uncontrolled hypertension (systolic blood pressure at rest ≥ 180 mmHg 
or diastolic blood pressure ≥ 100 mmHg); severe liver disease and severe renal impairment 
(creatinine clearance ≤ 30 ml/min); electrolyte disorders; uncontrolled thyroid disease and 
pregnancy. All patients signed informed consent prior to randomization. The study was designed 
according to the principles outlined in the Declaration of Helsinki and was approved by the Ethics 
Committee and Institutional Review. 
 
 

Study design and Treatment 
All patients with CCS I-III angina, were considered and only patients who met the inclusion 
criteria, after signing the informed consent form, were included in our study. The treatment was 
assigned on the basis of a 1:1 ratio to receive Ivabradine 5 mg twice daily (Ivabradine Group, IG) or 
standard therapy according to the guidelines (Control Group, CG). Both therapeutic strategies were 
titrated to the maximum tolerated dose, in particular β-blockers. All patients were submitted to 
clinical evaluation and exercise stress echocardiography at enrollment time (T1) and after 30 days 
of therapy (T2). During the period between exercise stress tests, clinical evaluation with ivabradine 
therapy up-titration was performed after 15 days. 
Patient evaluation included physical examination, HR measurement by 12-lead electrocardiograms 
(ECG), two-dimensional, Doppler and Tissue Doppler echocardiography, using Philips iE33 system 
(Andover, Massachusetts, USA) and a supine bicycle ergometer stress test. During the test, 
operators recorded echocardiograms before and during the exercise. The parameters measured were: 
left ventricular (LV) 2D diameters, systolic function parameters, ejection time, LV end-systolic and 
end-diastolic volumes in relation to body surface area (end-diastolic and end-systolic indices [EDI 
and ESI]), and LV ejection fraction (LVEF) were assessed according to Simpson’s method (as 
suggested by the American Society of Echocardiography and European Association of 
Echocardiography) [11]. 
Bicycle Stress Test. Exercise test, was performed using a semi-recumbent and tilting bicycle 
ergometer (X-SCRIBE EKG Analysis, Mortara Instruments; Ergometrics 800s, Ergoline West-
Germany) with an initial workload set at 25 Watt and increments of 25Watt/ 2 min. HR and rhythm 
is continuously recorded using a 12-lead electrocardiogram, blood pressure was measured at 
baseline, at peak exercise, and during the last minute of each stage including recovery. 
The rate of exercise, which was measured in metabolic equivalents (1 metabolic equivalent = 3.6 
ml/kg/min), and the duration of exercise were assessed as well. 
Chronotropic reserve was estimated using the formula: 100 × (peak HR–resting HR) / (220–age) – 
resting HR. 

Stress test was interrupted if the patient developed chest pain, ST segment elevation > 0.1 mV at 80 
ms from the J point, or a significant adverse event (significant ventricular arrhythmia, limiting 
breathlessness, dizziness, muscular exhaustion, chest pain, arterial pressure drop ≥ 10 mmHg with 
symptoms, or severe systemic hypertension). 
Echocardiography. Images were acquired in standard views and displayed side by side in a quad-
screen format. All images were digitally recorded in continuous-loop format. Total work at the 
ischemic threshold and peak exercise were calculated. Double product (DP) was calculated during 
the last stage of exercise performed by multiplying maximum systolic BP by maximum HR; triple 
product (TP), was obtained integrating DP with ejection time (ET) measured with mitral annular 
PW-TDI (BP x SBP x ET). 
In addition diastolic function was evaluated by PW Doppler E and A waves, TDI derived E’ 
measurements and E/E’ ratio. Mitral annular E’ velocity was estimated as the average between 
lateral and septal velocity. 
Drugs with possible interactions with ivabradine such as non-dihydropyridine calcium channel 
blockers, class I antiarrhythmics and strong inhibitors of cytochrome P450 3A4, were not allowed, 
whereas short-acting nitrates were allowed up to 3 hours before exercise or after exercise if needed. 
At the end of the tests, double, triple products and diastolic function evaluation, were collected by a 
blind operator. 
All parameters recorded and calculated in off-line analysis were included in our register. 
Statistical analysis. 
The sample size was not calculated because it was a pilot study. Continuous variables were 
presented as mean ± standard deviation (SD) and categorical variables as percentages. Categorical 
variables were compared among groups using the chi-square test or Fisher’s exact test when 
appropriate, whereas continuous variables were compared with Student t-test. All tests were two-
sided and a p value less than 0.05 was considered statistically significant. All analyses were 
performed using SPSS software, version 20.0 for Windows. 
 

COMPLIANCE WITH ETHICAL STANDARDS 
 
All authors declare that they have no conflict of interests. No funding was received for this study. 
All procedures performed in studies involving human participants were in accordance with the 
ethical standards of the institutional and national research committee and with the 1964 Helsinki 
declaration and its later amendments or comparable ethical standards. This article does not contain 
any studies with animals performed by any of the authors. Informed consent was obtained from all 
individual participants included in the study. 
 
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