Effects of Ivabradine in Mitral Valve Prolapse

Transcription

1 Original Article Effects of Ivabradine in Mitral Valve Prolapse Acta Cardiol Sin 2010;26:253 8 Electrophysiology Effects of a Novel I(f) Inhibitor; Ivabradine, on the Biochemical, Hemodynamic, and Electrophysiological Parameters in Symptomatic Patients with Mitral Valve Prolapse Davran Cicek, 1 H. Olcay Eldem, 1 Nihat Kalay, 2 Bulent Ozin 3 and Haldun Muderrisoglu 3 Introduction: We aimed to investigate the effects of ivabradine in symptomatic (sinus tachycardia) patients with mitral valve prolapse. Ivabradine specifically inhibits the If current in the sinoatrial node to lower heart rate without affecting other aspects of cardiac function. Methods: The study included 48 MVP patients. After 2 weeks of wash-out, echocardiographic, electrocardiographic, 24-hour Holter, and routine blood examinations were conducted. Ivabradine therapy was started at a dosage of 5 mg twice daily. After 1 mo of treatment, the abovementioned examinations were repeated. Results: The treatment was completed by 45 patients. No significant differences were observed between the preand post-treatment values of the echocardiographic, hemodynamic, and electrophysiological parameters. However, the symptom periods ( vs ; p = 0.003) and the maximum ( vs ; p = 0.001), mean (85 8vs.77 8; p = 0.002), and minimum heart rates (61 3vs.52 5; p = 0.001) recorded by Holter monitoring were significantly reduced. Conclusion: Ivabradine is effective and safe to relieve palpitation symptoms due to sinus tachycardia in patients with mitral valve prolapse. However, its safety in the longer term will require additional assessment. Key Words: Antiarrhythmic Cardiac pharmacology Ion channels Mitral valve prolapse Tachycardia Mitral valve prolapse (MVP), defined as echocardiographic (ECHO), angiographic, and pathologic protrusion of the mitral leaflets into the left atrium during systole, affects approximately 5% of the population worldwide. It was first recognized in the mid-1960s. 1-3 The typical symptoms that are associated with MVP are often a result of anxiety and autonomic dysfunction, and Received: April 13, 2010 Accepted: June 28, Department of Cardiology, Baskent University School of Medicine, Antalya; 2 Department of Cardiology, Erciyes University School of Medicine, Kayseri; 3 Department of Cardiology, Baskent University School of Medicine, Ankara. Address correspondence and reprint requests to: Dr. Davran Cicek, Department of Cardiology, Baskent University School of Medicine, Alanya, Antalya, Turkey. Tel: ; davrancicek@ mynet.com -adrenergic blockade helps alleviate them. 4 The conventional medical treatment for MVP involving palpitation due to sinus tachycardia is essentially based on -blockers. However, patient compliance with treatment is poor because of the side-effects of -blockers, such as bronchoconstriction and negative inotropic and hypotensive effects. Therefore, we considered the use of another agent that selectively reduces the heart rate by inhibiting the If pacemaker current, without the potentially harmful hemodynamic effects of -blockers. The If current is the major current underlying the spontaneous diastolic depolarization of the sinus node, 5-8 which is the fundamental mechanism at the origin of the spontaneous electrical activity of pacemaker cells. It is directly regulated by cyclic AMP (camp), a secondary messenger of the autonomic nervous system ad- 253 Acta Cardiol Sin 2010;26:253 8

2 Davran Cicek et al. renergic stimulation by an increase in the intracellular concentration of camp in pacemaker cells increases the If current and the slope of diastolic depolarization, which decreases the diastolic time and accelerates the heart rate; vagal stimulation has the opposite effects. Therefore, direct inhibition of the If current appears to be ideal in order to induce selective reduction of not only the resting heart rate but also tachycardia mediated by an increase in the sympathetic tone In the present study, we evaluated the effects of ivabradine used as an alternative to -blockers in MVP patients complaining of palpitations due to sinus tachycardia. METHODS This study protocol was approved by the ethics committee of Baskent University School of Medicine, Ankara. Informed consent was obtained from all the subjects enrolled in this clinical trial. The study included 48 symptomatic MVP patients who could not tolerate blocker treatment because of side effects; the patients were all aged over 16 years. The MVP criterion was valve prolapse 2 mm above the mitral annulus in the long-axis parasternal view. 13 No patient had a history of syncope or sustained ventricular tachycardia or a family history of sudden cardiac death, and none of the patients exhibited an accompanying cardiac or noncardiac disease or were under concomitant medication with any other drugs. After a 2-wk wash-out period for -blockers, all the patients underwent basal electrocardiographic examination (ECG), 24-h Holter recording, ECHO, and routine blood tests. The symptom period was defined as the number of events with sinus tachycardia, atrial or ventricular premature beats or supra-ventricular tachycardias including atrial fibrillation that were indicated during 24-h Holter recording in patients when they experienced palpitation. The heart rate and PR and corrected QT (QT C ) intervals were obtained from ECG. We corrected the QT time for heart rate using Bazett s Formula = QT Interval / ( RR interval ), RR Interval = 60/HR. Ejection fraction, left ventricular diameter, mitral E wave, mitral A wave, and left atrial and aortic measurements were obtained from ECHO. The counts of white blood cells and platelets and the levels of low-density lipoprotein, high-density lipoprotein, triglycerides, thyroid-stimulating hormone, free T4, and microalbuminuria were determined in the routine blood examination. Next, ivabradine (Coralan; Les Laboratoires Servier Industrie; Gidy, France) therapy was started for all the MVP patients at a dosage of 5 mg twice daily. After 1 mo of ivabradine treatment, the patients again underwent 24-h Holter recording, ECG examination, ECHO, and routine blood tests. The 24-hour Holter recordings were obtained on a 7-channel recorder (DMS Holter Recorder; MTM Multitechmed GmbH; Germany). Data that were recorded for 16 h and were of suitable quality for evaluation were analyzed. If these criteria were not met, the data were recorded again. Statistical analysis Quantitative variables were expressed as mean standard deviation, and discrete variables were expressed as percentages. The paired t test was used to investigate changes, with time as a dependent variable. The SPSS 11.0 (SPSS Inc.; Chicago, IL) statistical software package was used for analysis. A p value < 0.05 was considered statistically significant. RESULTS Of the 48 symptomatic MVP patients, 45 (94%) lasted through the 1-mo treatment period; 36 (80%) were female, and 9 (20%) were male. Their mean age was yr. Three patients withdrew from ivabradine therapy because they presented vision symptoms. The symptom periods obtained by 24-h Holter recording were found to have decreased significantly ( vs events/24 h; p = 0.003). Biochemical effects The biochemical effects of ivabradine are shown in Table 1. No significant difference was observed in the hematologic parameters, cholesterol levels, and thyroid hormone levels after ivabradine treatment. Hemodynamic effects The effects of ivabradine on the echocardiographic parameters and blood pressure are shown in Table 2. No significant difference was observed between the baseline Acta Cardiol Sin 2010;26:

3 Effects of Ivabradine in Mitral Valve Prolapse and post-treatment systolic ( vs mmhg; p = 0.1) and diastolic (69 10 vs mmhg; p = 0.05) blood pressures. Further, no difference was noted in the echocardiographic parameters after treatment. Electrocardiographic effects The effects of ivabradine on the electrocardiographic parameters are shown in Table 3. The symptom periods ( vs ; p = 0.003), office heart rate measurements (82 15 vs bpm; p = 0.001) (Figures 1A, B), and the maximum ( vs bpm; p = 0.001), mean (85 8vs.77 8 bpm; p = 0.002), and minimum heart rates (61 3vs.52 5 bpm; p = 0.001) recorded by Holter monitoring were significantly decreased after treatment. As observed in the case of our study (see Figure 1), the QT interval was pro- Table 1. Biochemical effects of ivabradine Baseline 1 month p value Hgb (g/dl) WBC (c/mm3) PLT (c/mm3) LDL (mg/dl) HDL (mg/dl) TG (mg/dl) FT4 (ng/dl) TSH (IU/ml) Microalbuminuria (mg/l) Creatinin (mg/dl) FT4, freet4; Hgb, hemoglobin; HDL, high-density lipoprotein; LDL, low-density lipoprotein; TG, triglycerides; TSH, thyroidstimulating hormone; PLT, platelets; WBC, white blood cells. Table 2. Effects of ivabradine on echocardiographic parameters and blood pressure Baseline 1 month p value Systolic BP (mmhg) Diastolic BP (mmhg) Ejection fraction (%) LVDD (mm) LVSD (mm) Mitral E wave (m/s) Mitral A wave (m/s) Left atrium (mm) Aorta (mm) BP, blood pressure; LVDD, left ventricular diastolic diameter; LVSD, left ventricular systolic diameter. Table 3. Effects of ivabradine on ECG parameters Baseline 1 month p value Office HR b.p.m PR interval (ms) QTc interval (ms) Maximum HR b.p.m Mean HR b.p.m Minimum HR b.p.m Symptom periods b.p.m., beats per minute; ECG, electrocardiography; HR, heart rate; QTc, corrected QT. 255 Acta Cardiol Sin 2010;26:253 8

4 Davran Cicek et al. A B Figure 1. Electrocardiograpy of a 28-year-old female patient before (A) and after (B) ivabradine treatment. Heart rate decreased to 72 bpm from 112 bpm and the QT interval was prolonged (379 ms to 392 ms) as expected, but after appropriate correction for heart rate, no significant effect of ivabradine on QT interval (QTc) was observed. MVP patients who have palpitations due to sinus tachycardia. Ivabradine is a new drug that lowers the sinus rate, and its safety and efficacy have been studied in multiple trials. During the clinical development of ivabradine, Savelieva et al. showed that ivabradine has a good safety profile via clinical studies involving more than 3500 patients and 800 healthy volunteers. 14 The most common adverse events were vision symptoms (blurred vision, diplopia, etc.) in 16.4% of patients and sinus bradycardia of 55 bpm or less in 3.2% of patients longed as expected, but no significant effect of ivabradine on ventricular repolarization duration was demonstrated once the appropriate correction for heart rate (i.e., QTc interval) was made and compared (see Table 3). DISCUSSION To our knowledge, this is the first clinical trial of the novel selective If inhibitor ivabradine in symptomatic Acta Cardiol Sin 2010;26:

5 Effects of Ivabradine in Mitral Valve Prolapse treated with the recommended dosages of 5 and 7.5 mg twice daily. Less than 1% of patients withdrew from therapy because of sinus bradycardia. As observed in the case of our study, the QT interval was prolonged as expected, but no significant effect of ivabradine on ventricular repolarization duration was demonstrated once the appropriate correction for heart rate was made and the QT intervals were directly compared. Vision symptoms are transient and do not affect the quality of life. Further, it was found that they led to few withdrawals (< 1%; 24 of 2545 patients) and resolved during treatment in 77.5% (383 of 491) patients. Ivabradine does not affect other tissues. 14 The common adverse events were vision symptoms in our study group as well (6.25%). Further, the vision symptoms were once again transient, but the patients withdrew from treatment nonetheless. The QTc and PR intervals were not significantly altered. The clinical development of ivabradine has been carried out on the basis of these and other preclinical data which indicate that by inhibiting the If pacemaker current of the sinus node, this drug can selectively reduce the heart rate, both at rest and during exercise, with a twice-daily dosing regimen. 14,15 Further, it does not modify myocardial contractility, atrioventricular conduction, or ventricular repolarization, and it could be, by its sole hemodynamic effect at least, as potent as a blocker in preventing myocardial ischemia while offering better protection for regional myocardial contractility The anti-ischemic and anti-anginal effects of ivabradine induced by a reduction in the heart rate have been confirmed in multiple trials The BEAUTIFUL study 19 was designed to examine whether ivabradine could decrease the incidence of cardiovascular events in patients with coronary artery disease and left ventricular systolic dysfunction (LVSD). The results, which have been published, 20,21 showed no benefits of ivabradine. However, in a subgroup of patients who had a heart rate of 70 bpm or more, the incidence of fatal and nonfatal myocardial infarction (MI) and coronary revascularization was reduced. The BEAUTIFUL study also showed that ivabradine could be safely used in the other subgroup of patients. In our trial, we observed that the mean heart rate reduced by 8 bpm after 1 mo of treatment. The maximum and minimum heart rates were also significantly decreased. Ivabradine had no effect on the blood pressure and ejection fraction. These findings indicate that ivabradine can be used as an alternative to -blockers to treat symptomatic MVP patients who exhibit the sideeffects of the latter. This study has several limitations, of which the small number of patients, lack of direct randomization, and short follow-up period are the main ones. Also the effects of ivabradine on heart rate variability, which was not specifically evaluated in this study, deserve further investigation. CONCLUSION Ivabradine can be used as an alternative treatment for symptomatic MVP patients who cannot tolerate -blockers. However, the longer-term safety of ivabradine requires additional assessment. ACKNOWLEDGEMENTS All support for this study came from institutional and departmental resources. REFERENCES 1. Barlow JB, Bosman CK, Pocock WA, et al. Late systolic murmurs and non-ejection ( mid late ) systolic clicks. Br Heart J 1968;30: Jeresaty RM. Mitral Valve Prolapse. New York, Raven Press, Cheitlin MD, Byrd RC. The click-murmur syndrome: a clinical problem in diagnosis and treatment. JAMA 1981;245: Boudoulas H, Wooley CF. Floppy mitral valve/mitral valve prolaps/mitral valvular regurgitation: effects on the circulation. J Cardiol 2001;37: DiFrancesco D, Ferroni A, Mazzanti M, et al. Properties of the hyperpolarizing-activated current (If) in cells isolated from the rabbit sino-atrial node. J Physiol (Lond) 1986;377: DiFrancesco D. The contribution of the pacemaker current (If) to generation of spontaneous activity in rabbit sino-atrial node myocytes. J Physiol 1991;434: DiFrancesco D. The onset and autonomic regulation of cardiac pacemaker activity: relevance of the current. Cardiovasc Res 1995;29: DiFrancesco D. The pacemaker current (If) plays an important role in regulating SA node pacemaker activity. Cardiovasc Res 257 Acta Cardiol Sin 2010;26:253 8

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