Oral Ivabradine Research Articles

Reducing Elevated Heart Rates in Patients with Multiple Organ Dysfunction Syndrome with The If (Funny Channel Current) Inhibitor Ivabradine.

A heart rate higher than 90 beats/min indicates an unfavorable prognosis for patients with multiple organ dysfunction syndrome (MODS). We sought to investigate the effect of the pacemaker current (If) inhibitor ivabradine on heart rate, hemodynamics, and disease severity among patients with MODS. In this prospective, controlled, randomized, open-label, two-arm phase II trial, 70 patients with MODS, a sinus rhythm of at least 90 beats/min, and contraindications to β-blocker therapy were randomly assigned to receive the standard treatment ± ivabradine (5 mg twice daily) for 96 h via the enteral route. The primary outcome was the percentage of patients with a heart rate reduction of at least 10 beats/min after 96 h. Secondary outcomes included the effect of ivabradine on hemodynamics, disease severity, vasopressor use, mortality, and adverse events. There were no significant differences in the primary outcome between the ivabradine and control groups (P = 0.147). After 96 h, the daily median heart rate was reduced by 7 beats/min in the control group and by 16 beats/min in the ivabradine group (P = 0.014). No differences in secondary outcomes were observed. The number of critically ill patients with MODS and a sinus rhythm of at least 90 beats/min that experienced a heart rate reduction of at least 10 beats/min after oral ivabradine treatment did not differ significantly between groups. The moderate but significant reduction of heart rate by 7 beats/min did not affect hemodynamics or disease severity.

Acute effect of ivabradine on heart rate and myocardial oxygen consumption in dogs with asymptomatic mitral valve degeneration.

Degenerative mitral valve disease (DMVD) is a common cardiac disease in geriatric dogs characterized by the degeneration of the mitral valve, leading to decreased cardiac output and activation of the sympathetic and renin-angiotensin-aldosterone system. This disease results in an increased resting heart rate (HR) and myocardial oxygen consumption (MVO2). A recent publication demonstrated that dogs with asymptomatic DMVD had a significantly higher HR and systemic blood pressure (BP) than age-matched control dogs. This higher HR will eventually contribute to increased MVO2. This study aimed to determine the effects of a single oral dose of ivabradine on the HR, MVO2 as assessed by the rate-pressure product, and BP in dogs with asymptomatic DMVD. Seven beagles with naturally occurring DMVD were instrumented by the Holter recorder and an oscillometric device to measure electrocardiogram and BP for 24 and 12 h, respectively. Each dog was randomly subjected to receive either placebo or ivabradine (0.5, 1.0 and 2.0 mg/kg). The results revealed that oral administration of ivabradine significantly decreased the HR and rate-pressure product in a dose-dependent manner without adverse effects. The highest dose of 2.0 mg/kg significantly reduced systolic and mean BP. Therefore, the findings imply that a single oral ivabradine administration at a dose of 1.0 mg/kg is suitable for dogs with asymptomatic DMVD to reduce the HR and MVO2 without marked effects on BP. This may potentially make ivabradine promising for management of an elevated HR in DMVD dogs.

Ivabradine versus propranolol given orally in microlaryngoscopic surgeries in attenuating stress response: A comparative prospective double blind randomized study

Background and objectiveIn this study we evaluated oral ivabradine (a relatively new heart rate lowering agent) versus oral propranolol (a classic commonly used beta-blocker) in achieving a hemodynamic stability and controlling possible changes in blood glucose level due to stress response in microlaryngoscopic surgeries.MethodsA total of 50 American Society of Anesthesiologists (ASA) 1,2 patients scheduled for microlaryngoscopic surgeries were included in this prospective, randomized controlled double blind study. They were given either oral ivabradine (5 mg tablet) group I or oral propranolol (10 mg tablet) group P in the evening before the operation and 1 h before the induction of anesthesia. Hemodynamic variables (systolic, diastolic, mean blood pressure and heart rate) and blood glucose level were recorded perioperatively.ResultsThe changes in blood pressure and heart rate in both groups were mild after intubation, laryngoscope fixation for surgery and extubation but these changes in ivabradine group were significantly less than the changes in propranolol group (P < 0.05). No significant difference (P > 0.05) was found between both groups in blood glucose level perioperatively. No statistically significant complications were observed in both groups.ConclusionPremedication with 5 mg of oral ivabradine or 10 mg of oral propranolol before microlaryngoscopic surgeries was effective in achieving a good degree of hemodynamic stability but ivabradine was more effective. Both drugs didn’t show an obvious effect on blood glucose level perioperatively. No complications were recorded.

Ivabradine and AV conduction

Ivabradine is a heart rate reducing agent that selectively inhibits the If current in the sinus node, without affecting heart contractility, relaxation and peripheral vascular resistance [1]. The clinical efficacy and safety of ivabradine have been confirmed in majormorbidity andmortality studies in patients with heart failure and coronary artery disease. Because the If current is mainly present in the sinus node, the effects of ivabradine can be observed during sinus rhythm. However, recent experimental [2] and clinical observations suggest that ivabradine significantly reduces the ventricular rate during atrial fibrillation [3,4]. In the context of this new and very important data we wish to submit our observation regarding the effects of ivabradine on the AV-node during fixed atrial pacing. A 60-year-old patient with a mechanical mitral valve was admitted with new-onset typical atrial flutter. The patient's only medication was an oral anticoagulant. The following day bidirectional block was created across the right atrial isthmus using radiofrequency ablation. After the termination of flutter, pacing was performed from a lateral tricuspid annulus site and from a coronary sinus ostium site to demonstrate permanent bidirectional block. The patient was given 5 mg oral ivabradine (“off-label”) after the ablation. Ivabradine caused a significant AH time prolongation during fixed cycle length stimulation after 30 min (Fig. 1), whereas the HV time remained unchanged. After the procedure, Holter monitoring showed no bradycardia episodes.

English

BACKGROUND AND OBJECTIVES: Rapid and dramatic hemodynamic changes which adversely affect the patient may occur during laryngoscopy and intubation. The present study evaluates the effect of oral ivabradine on the hemodynamics during laryngoscopy and endotracheal intubation in patients undergoing surgical procedures under general anesthesia. METHODS: A prospective randomized, single blinded study was conducted in 50 ASA- I adult patients undergoing various procedures under general anesthesia. The patients were randomly divided into two groups. Patients in group I (test group) (n=25) received oral Ivabradine, 5mg one tab at 6.00pm on the evening before the day of surgery and one 5mg tab one hour before intubation. Patients in group II (control group) (n=25) received placebo. Hemodynamic variables were recorded from pre-operative period to 10 minutes after intubation. RESULTS: There was not a very significant increase in the hemodynamic parameters in response to laryngoscopy and intubation in the Test group, when compared to the control group and the minimal raise also returned to baseline immediately within a minute. INTERPRETATIONS AND CONCLUSION: Ivabradine is an extremely useful drug to prevent abnormal increase in heart rate and minimizes the extent of hypertension seen during laryngoscopy and endotracheal intubation.

Single dose ivabradine versus intravenous metoprolol for heart rate reduction before coronary computed tomography angiography (CCTA) in patients receiving long-term calcium channel-blocker therapy

In patients with contraindication for beta-blockers who are also under long-term calcium channel-blocker therapy for any reason, ivabradine may be used as an alternative treatment to achieve the target heart rate. To assess whether single dose oral ivabradine in patients referred for coronary computed tomography angiography (CCTA) is safe and can significantly decrease heart rate compared to intravenous (i.v.) metoprolol in patients receiving long-term calcium channel-blocker therapy. One-hundred and twenty patients who were under calcium channel-blocker therapy referred for CCTA were randomized to premedication with single dose (15 mg) ivabradine (n = 63) or i.v. metoprolol (5-10 mg) (n = 62). Hearth rate (HR) was assessed at admission (HR1), prescan (HR2), and during CCTA scan (HR3) for all patients. Blood pressure (BP) was measured before medication (BP1) and immediately before CCTA scan (BP2). Although the HR averages of two groups were not significantly different before medication (HRIv1 = 80 ± 7 bpm vs. HRβ1 = 81 ± 7 bpm; P = 0.42), significant HR reduction was observed in the ivabradine group (HRIv3 = 62 ± 7 bpm) when compared to the metoprolol group (HRβ3 = 66 ± 6 bpm; P = 0.001). Decreases in HR forivabradine (18 ± 6 bpm) was significantly higher than for metoprolol (15 ± 4 bpm; P = 0.003) without relevant side-effects. Ivabradine showed no significant effect on either systolic BP or diastolic BP (siBPIv1, 139 ± 10; siBPIv2, 138 ± 10; P = 0.260; diBPIv1, 81 ± 7; diBPIv2, 81 ± 6; P = 0.59). Nevertheless, metoprolol group demonstrated significant reduction in both SiBP and DiBP (siBPβ1, 136 ± 11; siBPβ2 130 ± 11; P < 0.001; diBPβ1, 81 ± 6; diBPβ2, 78 ± 6; P < 0.001). Single dose ivabradine is safe and significantly more effective than i.v. metoprolol in decreasing HR in patients under calcium channel-blocker therapy.

PM064 The introduction of individualised milrinone doses as a cost containment strategy for heart failure patients under a hospital-in-the-home service

O ST E R A B ST R A C T S Introduction: In patients whit advanced cardiac failure under inotropes drugs therapy(IT) the use of negative chronotropic agents like beta blockers, digoxyn or calcium blockers is very restricted Tachycardia above 100 beats pm reduce diastolic time and efficiency of intra aortic baloon conterpusation (IABP). We present our experience with oral ivabradine used to improve the efficiency of IABP in tachycardic acute heart failure patients. Objectives: To evaluate with Swan Ganz catether (SG) the hemodynamic effect of ivabradine used to reduce sinus tachycardia during IT and IABP. Methods: Between January 2011 and August 2013 were prospectively included patients in sinus rhythm with more than 100 heart beat pm admitted in to the U.A.I. critical cardiology unite with decompensated dilated ischemic cardiomyopathy. All patients treated with at least 10gmas/Kg/min of one or more IT (unchanged during measurement period). No less than 2,2 liters/m2 SG measered cardiac index. Optimized IABP setting remain unchanged durin measurement period. Were excluded patients in schock of others causes, infections, renal failure, anemia, requiring or mechanical ventilation support or whith acute digestive desease. SG measurements were performed one hour before and three hours after a single oral dosis of 15mg ivabradine. Results: The study included 22patients (12men). All whith miocardial infarction history. Age average of 65.5 years. Left ejection fraction average was 27.3%. Dose of intravenous inotropic drug average was 17.2Kg/w/min. Three hours after ivabradine heart rate decreased from 123+/-5 to 97+-5 (P0.0003) Increase cardiac output of 4452+-550 ml minute at 4925+-535 ml/min(p0.031). Increase in cardiac index without statistical significance of 2.21+/-0.3 to 2.37+/-0.3 liters/m (p0.08). The average stroke volume increased significantly from 33.9 +-5 to 52.3 +-8 ml(p0.0007). The left ventricule work index increased from 12.9 +-3 to 17.3 +-4 (p0.00003). No differences were observed in the records of right atrial pressure, wedge, systemic vascular and pulmonary resistance. After five ivabradine half-lives suspension no ecg or clinical adverse effects were observed. Conclusion: Ivabradine is useful to moderate sinus tachycardia an and improve efficiency of IABP in advanced heart failure. Ivabradine use did not interfere with IT showing an improvement in some cardiac output parameters. No changes were observed in preload and afterload parameters in this set of patients. No electrocardiographic or clinical adverse effects were observed. Disclosure of Interest: None Declared

Ivabradine: a guide to its use in chronic heart failure

Oral ivabradine (Procoralan®; Coralan®) is a useful option for the treatment of patients with symptomatic chronic heart failure with systolic dysfunction. It is the only specific If current inhibitor approved for use in chronic heart failure and in the treatment of coronary artery disease, and is available in various countries worldwide, including the EU and Australia. Ivabradine is a pure heart rate-lowering drug, without other direct cardiovascular effects. In the randomized, double-blind, placebo-controlled, multinational SHIFT trial, the risk of cardiovascular death or hospital admission for heart failure was significantly reduced by ivabradine; this was mainly driven by the reduction in heart failure hospitalizations. Beneficial effects were seen for various other outcomes, including the risk of death because of heart failure. Ivabradine was generally well tolerated, with bradycardia being one of the most commonly reported adverse events.

Heart Rate Reduction with Ivabradine in Patients with Acute Decompensated Systolic Heart Failure

In patients with acute decompensated systolic heart failure (ADSHF) high resting heart rate (HR) could be either a compensatory mechanism or contribute to worsening heart failure. The aim of this study was to evaluate, in patients with ADSHF and resting HR >70 bpm, the early (within 24 h) and late (at discharge) effects of oral administration of ivabradine on HR reduction. Ten consecutive patients with ADSHF, left ventricular ejection fraction <40 % and HR >70 bpm, without other acute conditions or inotropic therapy, began open-label treatment with oral ivabradine according to a pre-established Heart Failure Unit protocol. We obtained clinical and laboratory data at four periods: admission (T0), immediately before initiation of ivabradine (T2), 24 h after initiation of ivabradine (T3), and at discharge (T4). Ivabradine was administered in 60 % of the patients before the second day. HR decreased 10.7 ± 7.2 bpm at T3 (p < 0.001) and 16.3 ± 8.2 bpm at T4 (p = 0.002). The systolic blood pressure decreased at T3 (p = 0.012), returning to baseline values at T4. There was no change in diastolic and mean blood pressure. New York Heart Association (NYHA) class improvement by two levels was associated with lower HR at T4 (p = 0.033). HR and N-terminal pro-brain natriuretic peptide (Nt-ProBNP) at baseline correlated significantly [Spearman correlation coefficient (rs) = 0.789, p = 0.013]. Total Nt-ProBNP reduction correlated with the HR before (r = 0.762, p = 0.028) and after (T3: r = 0.647, p = 0.083; T4: r = 0.738, p = 0.037) ivabradine addition. In the present cohort of patients with ADSHF and HR >70 bpm, the selective reduction of HR with oral ivabradine was safe and efficient.

Comparison of different strategies of ivabradine premedication for heart rate reduction before coronary computed tomography angiography

ObjectiveThe aim of this study was to assess the effectiveness and safety of different strategies of ivabradine therapy by comparing the effects on heart rate (HR), blood pressure (BP), and image quality of coronary CT angiography (CTA). MethodsA total of 192 consecutive patients were randomly assigned to 3 groups of oral premedication with ivabradine 15 mg (single dose), 10 mg (single dose), and 5 mg twice daily for 5 days, prospectively. Patients using HR-lowering drugs and patients with β-blockade contraindication were excluded. The target HR was 65 beats/min. In addition 5 to 10 mg of intravenous metoprolol was administered to the patients at the CT unit, if required. The systolic and diastolic blood BP values and the HRs were recorded. Image quality was assessed for 8 of 15 coronary segments with a 4-point grading scale. Results were compared with the Kruskal-Wallis test, one-way ANOVA, and χ2 test. ResultsReductions in mean HR after the treatment were 18 ± 6, 14 ± 4, and 17 ± 7 beats/min for groups 1, 2, and 3, respectively. With the total additional therapies, 81.3%, 67.2%, and 84.3% of the patients achieved HR < 65 beats/min in groups 1, 2, and 3, respectively. The mean BP values before coronary CTA were not significantly changed except for patients in group 2. Unacceptable (score 0) image quality was obtained in only 4.5%, 10.2%, and 4.2% of all the coronary segments, in groups 1, 2, and 3, respectively. ConclusionsOur study indicates that coronary CTA with premedication with oral ivabradine in all 3 strategies is safe and effective in reducing HR, in particular with a β-blockade combination. All 3 ivabradine regimes may be an alternative strategy for HR lowering in patients undergoing coronary CTA. Ivabradine 15 mg (single dose) and ivabradine 5 mg twice daily for 5 days are superior to the ivabradine 10-mg single-dose regime for HR lowering without adjunctive intravenous β-blocker usage.

Effect of Ivabradine on Endothelial Function in Diastolic and Right Heart Failure Patients

Background. Ivabradine is an If ion current inhibitor that has proved to reduce mortality in patients with systolic heart failure by slowing heart rate without decreasing myocardial contractility. Photoplethysmography is a simple, low-cost optical technique that can evaluate vascular function and detect changes in blood flow, pulse, and swelling of tissular microvascular space. Objective. To evaluate the effect of ivabradine on endothelial function by photoplethysmography in diastolic and right heart failure patients. Methodology. 15 patients were included (mean age of 78.1 ± 9.2 years) with optimally treated diastolic and right heart failure. They underwent photoplethysmography before and after induced ischemia to evaluate the wave blood flow on the finger, using the maximum amplitude time/total time (MAT/TT) index. Two measurements were made before and after oral Ivabradine (mean 12.5 mg a day during 6 months of followup). Results. In the study group, the MAT/TT index was 29.1 ± 2.2 versus 24.3 ± 3.2 (P = 0.05) in basal recording and 30.4 ± 2.1 versus 23.3 ± 2.9 (P = 0.002), before versus after ischemia and before versus after Ivabradine intervention, respectively. Conclusions. Ivabradine administration improves endothelial function (shear stress) in diastolic and right heart failure patients.

Efficacy and Safety of Oral Ivabradine Versus Beta-blocker in Achieving Heart Rate Reduction Pre-Computed Tomography Coronary Angiogram (CTCA)

Efficacy and Safety of Oral Ivabradine Versus Beta-blocker in Achieving Heart Rate Reduction Pre-Computed Tomography Coronary Angiogram (CTCA)

Heart rate control with oral ivabradine in computed tomography coronary angiography: A randomized comparison of 7.5 mg vs 5 mg regimen

BackgroundHeart rate (HR) reduction is essential to achieve optimal image quality and diagnostic accuracy with computed tomography coronary angiography (CTCA). Administration of oral ivabradine seems to be more effective than beta-blockade in reducing HR in patients referred for CTCA. MethodsTwo-hundred-fifty-nine consecutive patients referred for CTCA were prospectively enrolled. Patients not receiving beta-blocker at baseline (group 1) and those with beta-blocker therapy (group 2) were enrolled in the study. Each group was randomized into 3 parallel arms with 1:1:1 allocation. Patients who did not receive beta-blocker at baseline: underwent CTCA without beta blocker (n=49), and received ivabradine 5mg (n=48), or 7.5mg ivabradine (n=48). Patients with beta-blocker therapy: continued with the prior beta-blocker without any dose modification (n=38), and received ivabradine 5mg (n=38), or ivabradine 7.5mg (n=38). ResultsHR and blood pressure were assessed at admission (T0), immediately before CTCA (T1) and during CTCA (T2). Administration of ivabradine 7.5mg significantly reduced mean relative HR at T1 and T2 (p<0.01), the rate of patients not achieving target HR at T1 (p<0.001) and T2 (p<0.01), and the percentage of patients needing additional IV beta-blockade prior to CTCA (p<0.01). Results remained statistically significant even after correction for age, gender, ejection fraction, risk factors and HR at T0, in a multivariable analysis. ConclusionsIvabradine 7.5mg is more effective than ivabradine 5mg in increasing the rate of patients at target HR in patients referred for CTCA.

COMPARISON OF ORAL IVABRADINE AND METOPROLOL FOR CONTROL OF HEART RATE IN PATIENTS UNDERGOING CT CORONARY ANGIOGRAPHY

ObjectivesOptimisation of heart rate (HR) to limit motion artefacts is mandatory in all patients undergoing CT coronary angiography (CTCA). Despite use of β-blockers (ββ), patients often have HR>target range of...

Safety and efficacy of oral ivabradine as a heart rate-reducing agent in patients undergoing CT coronary angiography

To investigate the role of oral ivabradine as a heart rate reducing agent in patients undergoing CT coronary angiography (CTCA). Despite the routine use of β-blockers prior to CTCA studies, it is not uncommon to have patients with heart rates persistently above the target range of 65 bpm. Ivabradine is a selective inhibitor of the I(f) current, which primarily contributes to sinus node pacemaker activity, and has no significant direct cardiovascular effects such as reduction of blood pressure, cardiac contractility or impairment of cardiac conduction. We investigated 100 consecutive patients who had been referred for CTCA for the evaluation of suspected coronary artery disease (CAD). Patients were randomised to receive either of the following two pre-medication protocols: oral metorprolol or oral ivabradine. Ivabradine was significantly more effective than metorprolol in lowering the heart rate; the mean percentage reduction in heart rate with ivabradine vs metorpolol was 23.89+6.95% vs 15.20+4.50%, respectively (p=0.0001). Metoprolol significantly lowered both systolic and diastolic blood pressure while ivabradine did not. The requirement of additional doses to achieve a target heart rate of <65 beats per min was also significantly more frequent with metoprolol. Ivabradine is a potentially attractive alternative to currently used drugs for reduction of heart rate in patients undergoing CTCA.

Lasting reduction of heart transplant tachycardia with ivabradine is effective and well tolerated: results of 48-month study

The safety and efficacy of ivabradine applied in heart transplant (HTx) recipients with permanent sinus tachycardia (PST) has been depicted in previous short-term follow-up studies. We sought to investigate the long-term impact of ivabradine in this patient population. From May to November 2006, 29 HTx recipients with PST, who exhibited either contraindications or intolerance of beta-blocker medication or insufficient heart rate (HR) reduction on beta-blocker treatment, first received oral ivabradine treatment (5 mg bid). Ivabradine treatment was discontinued in three patients due to adverse events within the first week. In the remaining 26 patients, resting HR was significantly lowered from 106.8 ± 9.2 at baseline to 83.2 ± 5.1 bpm after 3 months (p < 0.001). This effect remained stable in the long-term follow-up (82.1 ± 11.8 bpm after 4 years), whilst blood pressure was not affected. Apart from the corrected QT interval (QTc), there were no significant changes in ECG. The elongated QTc at baseline (469.4 ± 29.5 ms) decreased to 444.3 ± 33.1 ms after 3 months ivabradine treatment (p < 0.001). A decrease in QTc until month 9 was observed, followed by a partial increase to the upper limit of the normal value. Neither allograft rejection nor changes in left ventricular ejection fraction were observed over the follow-up period. In conclusion, ivabradine appears to be a safe and feasible long-term therapeutic option for HTx recipients with PST. It reduced the resting HR without impairment of blood pressure, myocardial contractility and cardiac conduction. The prognostic value of normalised QTc following ivabradine administration requires further observation.

Ivabradine usage in coronary CT angiography

The objective of our study was to assess the effect of ivabradine on image quality of ECG-gated multidetector computed tomography (MDCT) coronary angiography. Computed tomography coronary angiography (CTCA) was performed on two groups. In Group 1 (n=54), an intravenous beta-blocker was administered to patients with a heart rate >70 beats per minute (bpm) just before CTCA. In Group 2 (n=56), oral ivabradine 5 mg was administered twice a day for three days prior to CTCA examination to patients with a heart rate >70 bpm and contraindication to beta-blockers. Images acquired on two different MDCT scanners were scored in terms of image quality of the coronary artery segments using a 5-point grading scale (Grade 1, unreadable; Grade 5, excellent). The mean heart rates during CTCA were 64 ± 6.7 bpm for Group 1 and 59 ± 4.1 bpm for Group 2 (P < 0.05). Mean heart rate reduction was 9 ± 5% and 14 ± 8% for Groups 1 and 2, respectively (P < 0.001). A total of 880 segments were evaluated in 110 patients. When the best reconstruction interval was used, 89.8% and 95.5% of all the coronary segments showed acceptable image quality in Groups 1 and 2, respectively. Acceptable image quality of the middle right coronary artery was obtained in 78.3% of Group 1 and 92.4% of Group 2. These ratios for the other segments were 88.4% for Group 1 and 95.2% for Group 2. Reduction of heart rates with ivabradine premedication improves the image quality of CTCA. It should be considered as an alternative drug, particularly in patients with contraindications to beta-blockers.

Pharmacodynamic effects of ivabradine, a negative chronotropic agent, in healthy cats

Objective To determine the pharmacodynamic effects of oral ivabradine in cats. Animals Eight healthy, adult domestic short hair cats. Methods Each cat underwent four study periods of 24 h, receiving either one dose of placebo or ivabradine (0.1 mg/kg, 0.3 mg/kg, and 0.5 mg/kg) in a single-blind randomized crossover study. Clinical tolerance was assessed hourly for the first 8 h, at 12 h, and at the end of the 24-h study period. Heart rate and blood pressure were monitored continuously for 18–24 h via radiotelemetry after each treatment. Response to stress (acoustic startle) was studied before ( t = 0) and after treatment ( t = 4 h). Statistical comparisons were made using a linear mixed models and 1-way and 2-way repeated measures ANOVA. Results Heart rate (min −1) decreased significantly ( P < 0.05) in a dose-dependent manner with peak negative chronotropic effects observed 3 h after ivabradine (mean ± SD; placebo, 144 ± 20; ivabradine 0.1 mg/kg, 133 ± 22; ivabradine 0.3 mg/kg, 112 ± 20; and ivabradine 0.5 mg/kg, 104 ± 11). Heart rate (min −1) was still reduced ( P < 0.05) 12 h after ivabradine (0.3 mg/kg; 128 ± 18 and 0.5 mg/kg; 124 ± 16) compared to placebo (141 ± 21). The tachycardic response to acoustic startle was significantly ( P < 0.01) blunted at all 3 doses of ivabradine. Myocardial oxygen consumption estimated by the rate-pressure product was significantly reduced ( P < 0.05) for all doses of ivabradine. No effect of ivabradine on systolic, diastolic, and mean blood pressure was identified and no clinically discernable side effects were observed. Conclusion These findings indicate that a single oral dose of ivabradine predictably lowers heart rate, blunts the chronotropic response to stress, and is clinically well tolerated in healthy cats. This makes ivabradine potentially interesting in the treatment of feline heart disease where ischemia is of pathophysiologic importance.

Pharmacokinetics of oral ivabradine in healthy cats

A liquid chromatography-tandem mass spectrometry (LC-MS/MS) analytical method for the measurement of the novel heart rate-lowering drug ivabradine and its major metabolite, S-18982, was cross-validated in the plasma of eight healthy cats. Plasma concentrations were then determined after single and repeated oral administration of ivabradine. Individual plasma concentrations versus time from each cat were used in compartmental analysis using the commercially available software WinNonlin. Both ivabradine and S-18982 reached their maximum concentrations of 103.33 and 3.86 ng/mL within 1 h. Following repeated administration, areas under the plasma concentration-time curves for ivabradine and S-18982 did not significantly increase. Two-compartmental and one-compartmental models with first-order input and elimination provided the best fit to the data for ivabradine and S-18982, respectively. Both models were combined to produce a single 4-compartment model characterizing ivabradine and S-18982 pharmacokinetics. The results of this study indicate that repeated oral doses of ivabradine produced plasma drug concentrations suitable for 12-h dosing intervals in healthy cats. Furthermore, the analytical assay and combined ivabradine/S-18982 model provide tools for further evaluation of ivabradine pharmacokinetics and pharmacodynamics in future studies in cats.

Incremental value and safety of oral ivabradine for heart rate reduction in computed tomography coronary angiography

BackgroundHeart rate (HR) reduction is essential to achieve optimal image quality and diagnostic accuracy with computed tomography coronary angiography (CTCA). Administration of ivabradine could be an attractive alternative to beta-blockade to reduce HR. MethodsOne-hundred-twenty-three patients referred for CTCA were prospectively enrolled. Patients were divided in two groups depending on the absence or presence of chronic beta-blockade treatment. Within the two groups patients were randomized to either no additional premedication or oral ivabradine for 5days prior to CTCA. In presence of chronic beta-blockade therapy it was shifted to atenolol 50mg twice a day for 5days prior to CTCA. HR and blood pressure were assessed at admission (T0), immediately before CTCA (T1) and during CTCA (T2). The target HR was <65bpm. ResultsIvabradine significantly reduced HR during CTCA. Mean relative HR reduction was 15% for controls, 12% for chronic beta-blockade, 19% for ivabradine and 24% for both chronic beta-blockade and ivabradine at T2 (p for trend <0.001). The rate of patients who reached the target HR at T2 was 83% in controls, 71% with chronic beta-blockade, 97% with ivabradine and 97% with both (p for trend <0.05). The percentage of patients that needed additional IV beta-blockade at T1 decreased from 69% to 40% with ivabradine and 30% with both (p for trend <0.05). ConclusionsIvabradine is safe and effective in increasing the rate of patients at target HR and in reducing the need for additional IV beta-blockade in patients referred for CTCA.