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Original Articles: Clinical Transplantation

Heart Rate Reduction After Heart Transplantation With Beta-Blocker Versus the Selective If Channel Antagonist Ivabradine

Doesch, Andreas O.1,3; Celik, Sultan1; Ehlermann, Philipp1; Frankenstein, Lutz1; Zehelein, Jörg1; Koch, Achim2; Katus, Hugo A.1; Dengler, Thomas J.1

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doi: 10.1097/01.tp.0000285265.86954.80
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Abstract

Several epidemiological studies have shown an inverse correlation between resting heart rate and life expectancy in healthy humans (1–6). This relationship has also been addressed in patients with arterial hypertension, metabolic syndrome, and in patients with cardiovascular disease (7, 8). This correlation has not been studied in patients after heart transplantation (HTX), most of whom have considerably elevated heart rates due to allograft denervation, which can be associated with symptomatic discomfort.

Heart transplant populations show increased exercise capacity compared to the pretransplantation phase, which remains subnormal compared to age-matched controls and shows only a limited increase with time after transplantation (9–11). Exercise tolerance in cardiac transplant recipients is limited by cardiac denervation, which alters efficient control of heart rate and cardiac output during physical exercise (11, 12). Pharmacologic heart rate reduction with beta-blockers or L-type calcium channel antagonists may negatively affect exercise capacity after HTX. Beta-blocker treatment can be associated with excessive blood pressure reduction and other systemic effects such as deterioration of diabetes control or bronchospasm. Furthermore, both classes of drugs are prone to other unwanted side effects such as fatigue, ankle edema, gastrointestinal disturbances, atrioventricular block, and sexual dysfunction (13).

Ivabradine, a specific If channel antagonist, is a novel therapeutic agent offering an opportunity for selective heart rate reduction that has not previously been studied in heart transplant recipients. If is one of the most important ionic currents for regulating pacemaker activity in the sinoatrial node (13, 14). If channel blockade with ivabradine shows exclusive heart rate reduction by lowering the slope of diastolic depolarization, no limiting effects on inotropy, cardiac conduction, or peripheral vascular tone have been demonstrated. The aim of this study was to compare heart rate control, tolerability and short-term safety of ivabradine and beta-blocker (metoprolol succinate) in heart transplant recipients and to determine effects on exercise capacity.

PATIENTS AND METHODS

Patients

Eligible subjects were stable heart allograft recipients with sinus rhythm and a resting heart rate above 90 bpm on several measurements, complaining of mild discomfort caused by the tachycardia. Patients needed to be >6 months posttransplantation, free from acute rejection (mean time from last rejection-free biopsy 4.2±2.8 months) and infection, and on stable doses of immunosuppression. All patients were New York Heart Association symptom class I; left ventricular ejection fraction at baseline was greater than 55%. None of the patients had been on beta-blocker therapy after heart transplantation prior to the beginning of this study; before heart transplantation no specific beta-blocker intolerance had been reported. All patients had given written consent for participation in the study.

The study population comprised 25 patients: 21 (84%) males, mean age 54.3±12.1 years, mean time posttransplantation 4.7±4.1 years (Table 1). Detailed patient characteristics, comedication and baseline laboratory values are summarized in Tables 1 and 2. All patients were on stable doses of immunosuppression, with a combination of mycophenolate mofetil and a calcineurin-inhibitor (cyclosporine or tacrolimus) being the most common (Table 1). An average of 1.6 rejections of International Society for Heart and Lung Transplantation grade ≥2R (15), rejection associated with hemodynamic compromise, or rejection requiring specific antirejection therapy had been diagnosed per patient prior to study entry.

TABLE 1
TABLE 1:
Patient demographic and clinical characteristics at baseline
TABLE 2
TABLE 2:
Clinical and laboratory parameters at baseline and after beta-blocker/ivabradine therapy

Study Protocol

An open-label, prospective, nonrandomized, single-center trial was performed to study consecutively the effects of 8-week periods of therapy with metoprolol succinate (target dose: 190 mg/day) and ivabradine (target dose: 15 mg/day) compared to baseline measurements without medication in the same patients. Due to the fixed treatment sequence, beta-blocker therapy preceded ivabradine medication in all patients, separated by a 10-day washout period. All patients who completed the beta-blocker phase (n=21, due to 4 dropouts) were subsequently treated with ivabradine; patients intolerant of beta-blocker were also treated with ivabradine outside of this study and were not formally analyzed (Fig. 1 for details of sequential study design). Carryover effects after beta-blocker therapy were excluded by performing a baseline resting ECG before ivabradine treatment. At baseline and after each 8-week period of medication, mean heart rate (24-hour Holter monitoring), exercise capacity (bicycle spiroergometry; VO2 peak), laboratory parameters, resting blood pressure (sphygmomanometer), and patient self-reporting (questionnaire) were assessed. Standard Holter recordings were analyzed for mean heart rate (arithmetic mean of heart rate over recorded period), minimum heart rate (lowest heart rate recorded), and maximum heart rate (highest heart rate recorded). Four weeks before study entry all heart rate active drugs, clonidine (three patients) and diltiazem (2 patients), were discontinued and substituted by heart rate-neutral calcium antagonist amlodipine (n=4) or hydrochlorothiazide diuretic (n=1) to compensate for blood pressure control. Dosing of both study drugs was carefully escalated over a 4-week period according to the following protocol: metoprolol succinate (extended release): week 1, 47.5 mg/day; week 2, 95 mg/day; week 3, 142.5 mg/day; week 4, 190 mg/day in a single daily dose; ivabradine: week 1, 2.5 mg/day; week 2, 5 mg/day; week 3, 10 mg/day; week 4, 15 mg/day in 2–3 daily doses. The effect of metoprolol on blood pressure was compensated by omission of concomitant antihypertensive medication (calcium antagonist: 11 patients, diuretic: six patients, alpha-adrenergic blocker: three patients). In four patients, cessation of a second antihypertensive agent was required to keep blood pressure stable (diuretic: two patients, moxonidine: two patients). During ivabradine therapy, original antihypertensive therapy at baseline was reinstated.

FIGURE 1.
FIGURE 1.:
Study protocol. Timeline of sequential study protocol, timepoints of examinations indicated by arrows. Twenty patients completing both treatment periods were included for statistical per-protocol analysis. discont, number of patients discontinuing study medication. See Results for details.

Bicycle Spiroergometry

Bicycle spiroergometries were performed on an Oxycon Alpha system (Jaeger Toennis, Hoechberg, Germany); the protocol started at 0 W with a stepwise increase of 15 W/2 min. Exercise was terminated for fatigue or other standard parameters including limiting angina pectoris, ischemic electrocardiogram changes (ST depression ≥0.3 mV, ST elevation ≥0.1 mV), and complex arrhythmias (sustained ventricular tachycardia >30 s). Exercise tests were performed in the morning 1–2 hours after drug intake. Heart rate reached at maximal exercise was considered maximal exercise heart rate. No specific instructions for physical exercise training were given during the study course.

Patient Self-Assessment/Questionnaire

A basic survey of patient self-assessment was performed by questionnaire. Patients were asked to comment on the subjective perception of lower heart rate and the subjective impact of lower frequency on comfort and exercise tolerability. Patients were queried for adverse events and asked about medication effects and preferences by questionnaire. The questionnaire comprised the following questions:

  1. Is the slower heart rate under study medication appreciated/not appreciated/indifferent (not noticed)?
  2. Did you subjectively notice an improvement/a decrease/no change in exercise capacity in daily life?
  3. Would you choose to continue the current study medication (yes/no)?

Statistics

Statistical analyses were performed with Statistical Package for Social Sciences (SPSS Inc., Chicago, IL). Due to limited sample size and lack of normal distribution, nonparametric testing (two way: Wilcoxon signed rank test, chi-square test; three-way: Friedman test) was applied for comparisons between groups. P values of ≤0.05 were considered statistically significant.

RESULTS

Study Completion

A total of 25 patients were included in the study. During the course of the study, study drugs were discontinued in four patients during the initial metoprolol treatment period and in one patient during the subsequent ivabradine treatment period. Causes of discontinuation were tiredness (n=2, 8%), arthralgia (n=1, 4%), and sleeplessness (n=1, 4%) under beta-blocker administration and nausea (n=1, 4%) during ivabradine treatment (see Fig. 1 for details of sequential study design). Patients with metoprolol intolerance received ivabradine on a compassionate-use basis, but were excluded from study analysis.

Mean daily beta-blocker dose was 147.3±53.9 mg/day, with 60% of patients reaching the target dose of 190 mg/day. Mean ivabradine dose was 14.8±1.1 mg/day with 95% of patients reaching target dose. Full metoprolol dosage escalation was not achieved due to dizziness without obvious hypotension or bradycardia (three patients), gastrointestinal symptoms (three patients), and unspecific patient preference (two patients). Symptoms subsided after dose reduction to the previous dosing level and were not scored as adverse events or side effects.

Heart Rate

At baseline, mean heart rate was 96.5±7.0 bpm (median: 94 bpm) as assessed by 24-hour Holter monitoring. After 8 weeks of beta-blocker treatment, mean heart rate was reduced to 84.4±8.8 bpm (median: 82.5 bpm; P=0.0004 vs. baseline) compared to ivabradine with 76.2±8.9 bpm (median: 74 bpm; P=0.0001 vs. baseline and P=0.003 vs. beta-blocker; Fig. 2A). Absolute changes in mean heart rate under beta-blocker and ivabradine are displayed in Figure 2B and C. Relative reduction in mean heart rate of >10% was noted in 80% of patients under beta-blocker therapy and in 90% of patients during ivabradine medication (Fig. 2D). No clinical symptoms of bradycardia were observed during the course of study.

FIGURE 2.
FIGURE 2.:
Mean heart rate (on 24-hour Holter monitoring) under treatment with beta-blocker and ivabradine. (A) Mean heart rate during Holter monitoring in beats per minute (bpm) under no medication (baseline), beta-blocker treatment and ivabradine treatment (mean±SD and median values are shown). (B) Absolute change in mean heart rate (in bpm) under beta-blocker therapy vs. baseline (frequency histogram). (C) Absolute change in mean heart rate (in bpm) under ivabradine therapy vs. baseline (frequency histogram). (D) Relative change in mean heart rate under beta-blocker and ivabradine therapy vs. baseline, proportion of patients shown (heart rate changes >±10% are considered significant increase or decrease, respectively).

Minimum heart rate decreased from 76.3±7.2 bpm (median: 74 bpm) at baseline to 68.9±12.9 bpm (median: 66.5 bpm) under beta-blocker (P=0.02 vs. baseline) and 63.1±8.7 bpm (median: 61 bpm) under ivabradine (P=0.0001 vs. baseline, P=0.02 vs. beta-blocker). Maximum heart rate assessed by Holter monitor was also reduced from 127.6±11.7 bpm (median: 124 bpm) at baseline to 112.0±15.7 bpm (median: 109 bpm) under beta-blocker (P=0.004 vs. baseline) and 106.1± 11.2 bpm (median: 107 bpm) on ivabradine (P=0.0007 vs. baseline, P=0.11 vs. beta-blocker). Similar results were obtained when analyzing only patients on target doses of study drugs (n=12; data not shown).

Correlation of relative reduction in heart rate with baseline heart rate showed a statistical trend for both beta-blocker and ivabradine therapy (P=0.09, and P=0.10 respectively). No significant association was found between treatment-related changes in heart rate under beta-blocker or ivabradine with age, gender, time after transplantation, patient weight, and the presence of graft vasculopathy (all P=NS).

Exercise Capacity

Maximal exercise heart rate (baseline mean: 140.5± 12.5 bpm, median: 141 bpm) was significantly reduced under beta-blocker therapy (mean: 125.9±15.7, median: 120.5 bpm, [P=0.001 vs. baseline]) and ivabradine treatment (mean: 120.3±14.4, median: 120 bpm [P=0.0004 vs. baseline]), whereas the observed differences between beta-blocker and ivabradine were not statistically significant (P=0.21; Fig. 3A). Accordingly, exercise-induced increase in heart rate (i.e., difference between maximum heart rate under exercise and resting heart rate before exercise) was significantly higher with ivabradine medication than during beta-blocker therapy (ivabradine: 44.2±13.1 bpm, beta-blocker: 38.6±11.3 bpm, P=0.04).

FIGURE 3.
FIGURE 3.:
Maximal exercise heart rate and exercise capacity. (A) Maximal exercise heart rate in bpm under no medication, beta-blocker therapy, and ivabradine treatment (mean±SD and median values are shown). (B) Exercise capacity (VO2 peak) at baseline and under beta-blocker and ivabradine medication (mean±SD and median values are shown). (C) Relative change in VO2 peak under beta-blocker and ivabradine treatment (changes of VO2 peak >±10% are considered a significant increase and reduction, respectively). Proportion of patients is shown. (D) O2 pulse at baseline and under beta-blocker and ivabradine medication (mean±SD and median values are shown).

Exercise capacity was unchanged by either beta-blocker or ivabradine treatment. VO2 peak at baseline was 19.8±5.2 ml/min per kg bodyweight (median: 19.2); on beta-blocker: 20.1±5.5 (median: 18.5); on ivabradine: 19.6±3.3 (median: 18.7; P=NS; Fig. 3B). Similar rates of relevant changes in VO2 peak (>±10%) were seen: 55% of patients on beta-blocker treatment (35% increase, 20% decrease) compared to 45% of patients on ivabradine (25% increase, 20% decrease; Fig. 3C). Changes in exercise capacity did not correlate with heart rate reduction at rest or during exercise with either drug. Oxygen-pulse at peak exercise was significantly higher under beta-blocker and ivabradine compared to baseline (baseline: 11.1±2.0 ml/min per bpm; beta-blocker: 12.9±3.4 ml/min per bpm; ivabradine: 13.2±2.2 ml/min per bpm; both P<0.01 vs. baseline), with no significant difference between the two study drugs (P=0.79; Fig. 3D). Exercise levels reached during spiroergometry were moderately higher under beta-blocker (102.8±24.5 W, P=0.02) and ivabradine (101.3± 19.4 Watts, P=0.03) compared to baseline (94.5±23.4 Watts); no difference was noted between study drugs. No correlation of changes in exercise capacity with any demographic or clinical parameter could be established. Anaerobic threshold was reached in all exercise studies.

Adverse Events/Clinical and Laboratory Parameters

Mild adverse effects not requiring drug discontinuation were noted in 45% of patients on beta-blocker (excluding symptoms preventing further dose escalation, see “Study Completion”) and 20% on ivabradine (Table 3, P=0.09). No correlation of adverse events with the extent of heart rate reduction could be demonstrated. Transient visual symptoms were not observed despite active inquiry (13).

TABLE 3
TABLE 3:
Adverse events not requiring drug discontinuation

Excessive heart rate reduction by ivabradine (e.g., due to CYP3A4 inhibition by immunosuppressive drugs, especially cyclosporine) was not seen in this cohort. Ivabradine dose and absolute/relative reduction in heart rate did not differ between patients on a cyclosporine-containing (11 of 20, 55%) versus a cyclosporine-free (9 of 20, 45%) immunosuppressive regimen. Mean heart rate in patients on ivabradine with cyclosporine was 75.1±8.7 compared to 77.4±11.7 bpm with a cyclosporine-free protocol; for minimum heart rate, a similar relation was found: 62.6±7.8 bpm with cyclosporine versus 65.8±12.5 bpm cyclosporine-free (P=NS).

No changes were observed in immunosuppressive drug dosage or blood levels. Laboratory values including renal, hepatic function tests, and differential blood count did not show any statistically significant changes under study drug (Table 2). No statistically significant differences regarding systolic and diastolic blood pressure were observed under ivabradine and beta-blocker therapy (P=NS).

Patient Self-Assessment/Questionnaire

Overall recall for the questions of the basic self-assessment questionnaire was 75%. Fewer questionnaires were returned for the beta-blocker period; percentages shown relate to total number of answered questions. Pharmacologic heart rate reduction (“slower heart rate”) was noticed and positively appreciated by more patients when treated with ivabradine than during beta-blocker treatment (88.2% vs. 45.4%, P<0.05; Fig. 4A); enhanced subjective exercise capacity (“improved ability to exercise”) was reported by 64.7% of patients when on ivabradine treatment versus 10% during beta-blocker medication (P<0.01; Fig. 4B). A total of 77.7% of patients opted to continue ivabradine medication, whereas only 40% chose to continue beta-blocker therapy (P<0.05; Fig. 4C).

FIGURE 4.
FIGURE 4.:
Basic patient self-assessment by questionnaire, proportion of answered questions is shown (overall recall 75%). (A) Appreciation of slower heart rate by patients under beta-blocker vs. ivabradine treatment. (B) Subjective appreciation of change in exercise capacity under beta-blocker and ivabradine treatment. (C) Patient preference for study drug continuation. Patients were asked if they would chose to continue treatment with the respective study drug beyond the study period.

DISCUSSION

Multiple epidemiological studies present evidence linking increased resting heart rate to an elevated risk of (cardiovascular) mortality (3, 16, 17). Due to graft denervation, sinus tachycardia is of particular relevance in patients after HTX. Few data address therapy with beta-blockers or L-type calcium antagonists for heart rate control in patients after HTX and related questions of cardiac exercise adaptation and adverse systemic side effects in this patient group. By selective reduction of heart rate, ivabradine offers theoretical advantages and the possibility to study heart rate reduction separated from other cardiocirculatory effects providing unprecedented insight into cardiopulmonary physiology after HTX. The present study sequentially compares the effects of beta-blocker (metoprolol) and ivabradine on heart rate and exercise capacity in cardiac allograft recipients showing effective heart rate reduction with preserved exercise tolerance for both drugs, while ivabradine therapy appears to be associated with less side effects and higher patient preference.

Study Design

Despite its weaker effects on heart rate than, for example, atenolol, metoprolol was chosen as the reference beta-blocker in contrast to previous studies (13) because it is the most commonly used beta-blocker, improves prognosis in ischemic heart disease and heart failure, shows better patient tolerability, and has no relevant pharmacokinetic interactions with immunosuppressive drugs. To achieve an adequate effect on heart rate, a high final dose of 190 mg/day of metoprolol was projected in the study protocol compared to 15 mg/day of ivabradine. For optimal comparability and low incidence of side effects, slow-dose escalation over 4 weeks and a 10-day washout period between drugs was implemented. Despite the shortcomings of fixed sequential study of drugs (especially the potential bias on tolerability), the fixed sequence (beta-blocker before ivabradine) was chosen for safety deliberations in that adverse effects due to heart rate lowering (irrespective of the study drug) would occur first during treatment with an agent with a well-described spectrum of side effects (beta-blocker), potentially allowing better discrimination of heart rate-related side effects versus substance-specific adverse effects.

Heart Rate

Per protocol analysis of 20 patients completing both treatment periods showed significantly more pronounced heart rate reduction with ivabradine compared to beta-blockers (Fig. 2A). This was demonstrated for mean as well as minimum heart rate on Holter monitoring, whereas—similar to previous data—maximum heart rates during Holter recording were not different (13, 18). Similar results were obtained for the analysis of absolute and relative heart rate reduction (Fig. 2B–D). This difference between beta-blocker and ivabradine treatment may be due to the higher relative dose of ivabradine, as only 60% of patients reached the target does for metoprolol compared to >90% with ivabradine. Similar differences in heart rate reduction are, however, found when comparing only patients on target dose for both drugs, suggesting a higher bradycardic potential of ivabradine. Compared to previous trials (13, 18), the heart rate reduction in this patient cohort was more pronounced with ivabradine medication, reaching almost 40% in some patients. Possible explanations include higher ivabradine dose (15 mg vs. 10 mg) and the assessment of mean heart rate on Holter monitoring instead of resting heart rate at trough drug concentration. The physiology of patients after HTX may also be particularly sensitive to ivabradine action. Augmented ivabradine effects through enhanced serum concentration due to pharmacokinetic interaction (CYP3A4 inhibition by cyclosporine) appear unlikely as no significant additional effect on heart rate was found for patients on cyclosporine therapy compared to cyclosporine-free regimens. The relative extent of heart rate reduction on ivabradine and beta-blocker was proportional to the degree of sinus tachycardia without medication (statistical trend), in keeping with previous data and ivabradine mode of action (13, 14).

Exercise Capacity

Exercise capacity after HTX may be limited by cardiac denervation (9, 11, 12) and exaggerated sympathetic vasoconstriction (19), potentially compounded by bradycardic medication. Similar to previous studies, peak VO2 values in this cohort of relatively untrained heart transplant recipients were reduced compared to normal values in age- and sex-matched healthy controls (9, 11). Beta-blocker and ivabradine treatment led to comparable significant reduction in maximum exercise heart rate (Fig. 3A), corresponding to previous studies (13, 18). Accordingly, exercise-induced increase in heart rate was significantly higher under ivabradine medication, suggesting superior cardiac exercise adaptation. No limiting effects on exercise capacity (measured as peak VO2) were seen with ivabradine or beta-blocker (Fig. 3B). Similar proportions of patients improved their exercise capacity on beta-blocker or ivabradine (Fig. 3C), whereas only 20% of patients showed moderately reduced oxygen uptake. Oxygen pulse (O2 uptake per heartbeat) significantly increased under both study drugs, suggesting economization of exercise, paralleled by a moderate, significant increase in maximum workload (Fig. 3D).

The current data exclude a marked deleterious effect of heart rate reduction by beta-blocker/ivabradine medication on exercise capacity in transplant recipients with preserved systolic graft function. Future studies will have to evaluate ivabradine and beta-blockers in well-trained individuals after HTX as well as in cases of systolic dysfunction or severe restrictive physiology.

Clinical and Laboratory Parameters

In accordance to previous studies (13), no statistically significant differences in systolic and diastolic blood pressure were observed during both treatment periods underscoring adequate omission of antihypertensive drugs during beta-blocker phase and the lack of antihypertensive effects of ivabradine. No influence of ivabradine and beta-blocker therapy on immunosuppressive drug dosages and levels was noted, excluding major clinically relevant pharmacokinetic interactions with cyclosporine or other immunosuppressive agents. No increased rates of rejection or infection were seen during the study period (not shown). All laboratory safety parameters remained stable under therapy with beta-blocker and ivabradine (Table 2), but due to the short study protocol conclusions on chronic safety aspects are limited.

Adverse Effects

Drug discontinuation was more frequent during beta-blocker treatment than with ivabradine (4 versus 1 patient). Ivabradine was generally well tolerated and side effects were mild, however, due to the short study duration assessment of chronic adverse effects are not possible. Fewer side effects not requiring drug discontinuation and a different spectrum of adverse effects were seen under ivabradine (Table 3). The fixed sequence of study drug does not allow unbiased estimation of side effects for both drugs; however, all four patients intolerant of beta-blocker tolerated ivabradine well outside the study. The rate of side effects was generally comparable with other beta-blocker and ivabradine trials (13). Visual disturbances (phosphenes), previously reported in ∼15% of patients during ivabradine therapy (20, 21), were not described in the current study despite high ivabradine dose and active inquiry about this distinctive side effect. Possible explanations include small sample size, different pattern of metabolites due to CYP3A4 interaction, or interaction with other comedication.

Patient Self-Assessment

Heart rate reduction was appreciated by many patients, supporting the notion that heart rate reduction will not limit physical well-being in transplant recipients. Similar to objective spiroergometry data, subjective appreciation of individual exercise capability was not adversely affected by treatment with beta-blocker or ivabradine. Side-by-side comparison of patient preference for either drug treatment favored ivabradine (Fig. 4A, B). Considerably more patients also chose to continue medication with ivabradine versus beta-blocker (Fig. 4C), even in the presence of similar heart rate reduction—most likely as a direct consequence of the lower frequency of side effects.

CONCLUSION

Selective heart rate reduction via If channel antagonist is clinically feasible, safe, and effective in heart allograft recipients with preserved systolic function. Ivabradine appears to be better tolerated than beta-blocker therapy, possibly due to exclusive modulation of heart rate without major systemic effects. Although prognostic effects of heart rate reduction after HTX are unclear, the complex interaction of rejection, infection, inflammation, and mechanical stress caused by fibrosis or hypertrophy may render heart rate reduction prognostically beneficial already in transplant patients with fully preserved left-ventricular function. Tolerability and possible advantageous effects will have to be studied in patients with reduced left venticular function or severe restrictive physiology (e.g., due to gross hypertrophy); trials of ivabradine in systolic heart failure are currently underway (22).

Certainly, no general recommendation of ivabradine (or beta-blocker) administration after HTX can yet be derived from these findings. In addition, it needs to be emphasized that use of ivabradine in heart transplant patients with sinus tachycardia still represents off-label use of this drug. The present data suggest that ivabradine may offer relevant benefit in patients with symptomatic sinus tachycardia and should represent an excellent therapeutic option, especially in cases of beta-blocker intolerance.

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Keywords:

Sinus tachycardia; Heart transplantation; If channel antagonist; Ivabradine; Beta-blocker

© 2007 Lippincott Williams & Wilkins, Inc.