Effects of Ivabradine on 6-Minute Walk Test and Quality of Life in Patients with Previously Implanted CRT-D

Ismail Ates, MD, Asuman H. Yavuz, MD, […], and Mehmet G. Kaya, MD+7View all authors and affiliations

Volume 61, Issue 6

https://doi.org/10.2310/JIM.0b013e31829614f0

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Abstract

Background

We aimed to evaluate clinical effects of additional heart rate control by ivabradine on life quality score and 6-minute walking test in patients with previously implanted biventricular cardiac resynchronization therapy defibrillator (CRT-D) with ischemic heart failure under regular treatment.

Methods

Fifteen men and 14 women with a median age of 63 years (range, 48–79 years) were studied. Twenty-one patients were in New York Heart Association class II (8 patients were in class III), CRT-D implanted previously, and with resting heart rates greater than 70 beats per minute with sinus rhythm despite conventional medication. Patients were given 2.5- to 7.5-mg ivabradine orally twice a day, and drug dosage was titrated to decrease the patients’ average heart rate to 70 beats per minute. Before and 3 months after ivabradine treatment, all patients underwent extensive clinical, echocardiographic, and laboratory evaluation.

Results

Ivabradine treatment produced dose-dependent reductions in heart rate at rest and at peak exercise (91.9 ± 6.3 to 71.7 ± 4.8 and 114.4 ± 7.6 to 96.8 ± 4.8; P = 0.001 and P = 0.001, respectively). There were also significant improvements in life quality score (52.4 ± 9.5 to 37.9±7.8; P = 0.001) and 6-minute walking distance (278.7 ± 85.8 to 373.3 ± 94.0; P = 0.001) of patients. All patients with New York Heart Association class III became class II after 3 months of ivabradine treatment.

Conclusion

Heart rate reduction in a short-term period by ivabradine produced significant improvements in exercise capacity and life quality in patients with CRT-D and conventional therapy.

Heart failure has a significant impact on quality of life and prognosis. The prevalence of chronic heart failure has increased mainly owing to aging of the population and the longer survival of people after myocardial infarction.1,2 Clinical features of heart failure include dyspnea, fatigue, and reduced exercise tolerance. The severity of symptoms and exercise capacity is commonly defined by New York Heart Association (NYHA) classification, from mild to severe (I-IV).3,4 Heart failure is also associated with increased morbidity, mortality, significantly decreased quality of life, and high health care costs.5,6

Heart rate reduction is an important aspect of care in patients with heart failure, and β-blockers remain the therapy of choice in all patients. In the treatment trials of heart failure, it has been shown that magnitude of heart rate reduction is associated with a reduction in mortality.7 Beta-blockers reduce mortality and hospital admission for worsening heart failure.7,8 However, many patients with heart failure still do not receive a β-blocker or cannot tolerate therapeutic doses owing to adverse effects.

Despite improvements in treatment, patients with heart failure often have severe and persistent symptoms. In randomized multicenter trials with cardiac resynchronization therapy defibrillator (CRT-D), it has been shown that short-term improvements in hemodynamics9 and long-term improvements in functional status are possible.10 Meta-analyses suggest that the most efficacious option in patients with heart failure and low left ventricular ejection fraction (LVEF) is CRT-D.11–14

The Systolic Heart failure treatment with the If inhibitor ivabradine Trial (SHIFT) study of chronic heart failure has recently reported that heart rate reduction by ivabradine can reduce cardiovascular mortality or hospitalization by 18% in patients with chronic heart failure and left ventricular systolic dysfunction. Ivabradine is a specific inhibitor of the If ion current of the sinus node, which induces a selective and dose-dependent reduction in heart rate without effect on atrioventricular conduction or contractility.7 In this study, we aimed to evaluate the effect of additional heart rate control by ivabradine on Minnesota life quality score and 6-minute walking test in patients with ischemic heart failure with previously implanted CRT-D and under regular conventional treatment (as defined by the European Society of Cardiology guidelines).15

Materials and Methods

The study was performed in the Cardiology Department, Medical Park Hospital, in Antalya, Turkey. We evaluated retrospectively 120 patients with implanted CRT-D between June 2009 and September 2011. Data from the 120 patients were analyzed prospectively between September and December 2011. The CRT-D implantation criteria were the following: NYHA function classes III to IV despite optimal pharmacological treatment, LVEF of 35% or less, sinus rhythm, left ventricular (LV) dilatation but with varying definitions, and QRS duration of 120 milliseconds (ms) or longer / 130 ms or longer. We observed that 29 of the 120 patients become NYHA function classes II to III after CRT-D implantation but could not reach acceptable heart rates (average heart rate >80 beats per minute [bpm]). These were chosen to receive ivabradine.

Exclusion criteria were myocardial infarction during the previous 6 months, evidence of myocardial ischemia, or ventricular tachycardia on exercise testing, obstructive valvular heart disease, or inability to exercise for any other reason other than dyspnea or fatigue. All patients gave their written informed consent before inclusion. The study was performed in accordance with the ethical principles stated in the Declaration of Helsinki in 1964, as revised in Washington in 2002. The study was approved by the local ethical committee in our city.

The ivabradine dose at the beginning of the study was 5 mg twice daily. Seven days after, if the resting heart rate was more than 60 bpm, the ivabradine dose was increased to 7.5 mg twice daily. If the heart rate was between 50 and 60 bpm, the dose was maintained at 5 mg twice daily. If the resting heart rate was lower than 50 bpm or the patient had signs or symptoms related to bradycardia, the dose was reduced to 2.5 mg twice daily. All patients underwent extensive clinical, echocardiographic, and laboratory evaluation both before and after initiation of ivabradine treatment. Resting heart was measured by 12-lead electrocardiography in the supine position at baseline and 3 months after. Two-dimensional and Doppler echocardiography was performed before ivabradine treatment and 3 months’ follow-up to evaluate cardiac function and included measurements of left atrial diameter and LVEFs. Images were obtained using a 3.5-MHz transducer, at a depth of 16 cm: the parasternal (long and short axes) and apical (2- and 4-chamber images) views by using a commercially available echocardiographic system (VIVID 3, General Electric Vingmed Ultrasound, Milwaukee, WI).

The study was performed in our outpatient Cardiology Department, Medical Park Hospital, Antalya, between September and December 2011, so we analyzed data results from patients’ charts retrospectively. Physical examinations, weight changes, serum creatinine, and sodium (Na) levels (mEq/L) have been followed during study period. Glomerular filtrations were calculated by using Modification of Diet in Renal Disease formula (mL/min per 1.73 m2).16

Patients were exercised 3 hours after a light meal, at the same time of day, and at least 3 hours after any treatment. The walking test was conducted as described by McGavin et al.,17 but the timing was standardized to 6 minutes. The test was carried out in a level enclosed corridor 20 m long. Each patient was instructed to cover as much ground as possible in 6 minutes. Patients were told to walk continuously if possible but that they could slow down or stop if necessary. The aim was that at the end of the test, the patients believed that they could not have walked any further in the 6 minutes. Patients were encouraged as necessary and advised when they had walked 3 and 5 minutes. The test was repeated twice on the same day with at least 3 to 4 hours between tests. Peak exercise heart rate was defined as maximal heart rate during the 6-minute walking test.

Assessment of quality of life was performed using the Minnesota Living with Heart Failure Questionnaire.18

The SPSS version 17:0 statistical package for Windows (Statistical Package for Social Sciences, Chicago, IL) was used for statistical analysis. Continuous variables were expressed as mean ± SD and compared using the Student t test. Parametric variables such as age, echocardiographic values, and 6-minute walking tests were estimated as mean value and standard deviation. Wilcoxon signed rank tests were used to compare the differences between the baseline and the third month of ivabradine. All statistical tests were performed at P < 0.05 level.

Results

Fifteen men and 14 women with mean ± SD age of 63.8 ± 7.1 years (range, 48–79 years) were included in this study (Table 1). During the study period, ivabradine dose was increased to 15 mg/d in 2 patients and remained as 10 mg/d in 11 patients. The ivabradine dose was reduced to 5 mg/d in 12 patients and 7.5 mg/d in 4 patients during the study period so that bradycardia will not progress to the symptomatic bradycardia. No any other adverse events were observed.

Table 1 Demographic Values of Patients

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Most patients were in the NYHA class II (8 patients were in class III) and resting heart rates were 91.9 ± 6.3 bpm on average with sinus rhythm. The cause of congestive heart failure was coronary artery disease in origin. All patients were taking conventional therapy including diuretic (furosemide and spironolactone), acetylsalicylic acid, and maximum tolerated dose of β-blocker. Other treatments included angiotensin-converting enzyme inhibitors (25 patients) and angiotensin receptor blockers (4 patients; Table 2).

Table 2 Medications of Study Population

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The mean dose of ivabradine was 7.93 mg/d (range, 5–15 mg/d). Ivabradine treatment produced dose-dependent reductions in heart rate at rest and at peak exercise heart rate in the 6-minute walking test (91.9 ± 6.3 to 71.7 ± 4.8 and 114.4 ± 7.6 to 96.8 ± 4.8; P = 0.001 and P = 0.001, respectively; Fig. 1) and caused a 33% increase in 6-minute walking distance (278.7 ± 85.8 m to 373.3 ± 94.0 m; P = 0.001; Fig. 2) and statistically significant improvements in Minnesota life quality test score and (52.4 ± 9.5 to 37.9 ± 7.8; P = 0.001). All patients with NYHA class III become class II after 3 months of ivabradine treatment. However, there were no significant changes in LVEF (P = 0.230), Na level (mEq/L) (P = 0.326), and glomerular filtration rate (mL/min per 1.73 m2) (0.944) of patients after ivabradine treatment (Table 3).

Table 3 Effects of Ivabradine and Echocardiographic Characteristics

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Figure 1 Ivabradine treatment produced dose-dependent reductions in heart rate at rest and at peak exercise.

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Figure 2 Ivabradine caused significant improvements in Minnesota life quality test score and 33% increase in 6 minutes walking distance.

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Discussion

In the treatment trials of heart failure, it has been shown that the magnitude of heart rate reduction is associated with a reduction in mortality.7,8 Beta-blockers remain the therapy of choice in all patients with systolic heart failure, but they may worsen atrioventricular (AV) conduction. Despite the demonstrated safety and effectiveness of β-blockers, physician use and patient compliance may be somewhat limited by the adverse effects of this class of agents, which include fatigue, sexual dysfunction, depression, cold extremities, light-headedness, gastrointestinal disturbances, bronchospasm, and AV block.19–21

If, a mixed Na+-K+ inward current activated by hyperpolarization and modulated by the autonomic nervous system, is one of the most important ionic currents for regulating pacemaker activity in the sinoatrial node. Ivabradine, an If current inhibitor, is a selective heart rate–lowering agent that acts on the sinoatrial node without the undesired effect of hypotension.22 Ivabradine causes decrease of diastolic depolarization gradient causing a reduction in the intrinsic pacemaker activity of the sinoatrial node.23 Colin et al.24 investigated the effects of ivabradine and atenolol on left ventricular isovolumetric relaxation at rest and during treadmill exercise in chronically instrumented dogs. For a similar reduction in heart rate at rest and during exercise, ivabradine, in contrast to atenolol, did not exert any negative lusitropic effect. In addition, in contrast to β-blockers, ivabradine does not cause detrimental effects on coronary vasomotion.25

Ivabradine is indicated in the treatment of stable angina pectoris in patients with sinus rhythm in conjunction with β-blockers, and in the treatment of patients with chronic heart failure.6 In the The morbidity-mortality evaluation of the If inhibitor ivabradine in patients with coronary disease and left ventricular dysfunction (BEAUTIFUL) trial, patients with coronary artery disease and left ventricular dysfunction did not achieve a significant benefit in the primary end point, and only the coronary outcome, not the heart failure outcome, was improved.8 However, the SHIFT study has recently assessed that heart rate reduction by direct sinus node inhibition can reduce cardiovascular mortality or heart failure hospitalization by 18% in patients with chronic heart failure and left ventricular systolic dysfunction.7 There was an improvement in patient-reported global quality of life and in NYHA class.7 The positive effects of ivabradine on left ventricular remodeling and N-terminal pro-brain natriuretic peptide were demonstrated in the previous studies.26,27 In addition, in the SHIFT echocardiographic substudy, Tardif et al.28 showed that heart rate reduction with ivabradine reverses left ventricle remodeling in patients with heart failure and left ventricle systolic dysfunction. Pure heart rate reduction without effect on AV conduction obtained by ivabradine may be a valuable option to avoid detrimental effects of high heart rate despite full conventional therapy in patients who have CRT-D. Mulder et al. were the first to demonstrate preservation of cardiac output despite the decrease in heart rate after administration of ivabradine in a rat model of chronic heart failure. The authors hypothesized that prolongation of the diastolic phase through the administration of ivabradine increases left ventricular filling and thus enhances stroke volume despite heart rate reduction.29 In a corresponding clinical study, hemodynamic effects of ivabradine were evaluated in 10 patients with advanced heart failure (NYHA III). The authors reported an increase of stroke volume of up to 51% after initiation of ivabradine therapy.30 Another study, which was performed by Russian physicians, showed that 100 patients with NYHA class III chronic heart failure were given metoprolol succinate alone or ivabradine alone if β-blocker use was not possible. Therapy with the use of ivabradine improved structural and functional state of the myocardium, elevated tolerance to exercise, caused positive changes of N-terminal pro-brain natriuretic peptide concentration in blood plasma and maximal oxygen volume during incremental exercise.31

The main finding from our study is that long-term heart rate reduction by ivabradine produced significant improvements in 6-minute walking test, 33% increase, and Minnesota life quality in patients previously implanted with CRT-D and using β-blocker. Additionally, there were no observed adverse effects of ivabradine. Despite recommendation to titrate β-blockers to full dosages, data in clinical practice reveal substantial underdosing of all β-blockers, with dosages generally 50% less than the dosages that randomized trials have proved to be effective.32 Thus, in patients who cannot be given higher doses of β-blockers or in whom sufficient heart rate reduction cannot be achieved, the combination with ivabradine seems to be an appropriate-therapeutic option.

Possible limitations of the present study are retrospective design, a single-center experience, and may be represented by the small number of patients. Additionally, absence of benefit seen in the echo parameters conversely to other studies is another limitation of the present study, which could be related to the small sample size and the short duration of the study. However, our population contains homogeneous unselected patients, therefore mirroring the real-world scenario.

To our knowledge, our study demonstrated for the first time that long-term heart rate reduction by ivabradine produced significant improvements in 6-minute walking test and life quality in patients previously implanted with CRT-D and using β-blocker in sinus rhythm who are in NYHA class II or III heart failure. Further studies are needed to evaluate the use of ivabradine to control heart rate in CRT-D recipients with moderate to severe left ventricular dysfunction.

Acknowledgments

The authors acknowledge the revision of Guy Neild, MD, and the assistance of the clinical technicians and clinical heart failure team that helped make this study possible.

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