Comparative effectiveness of metoprolol, ivabradine, and its combination in the management of inappropriate sinus tachycardia in coronary artery bypass graft patients.

BACKGROUND: Inappropriate sinus tachycardia (IST) is an arrhythmic complication observed after coronary artery bypass graft (CABG) surgery which left untreated, commonly increases chances of postoperative stroke. The primary study objective was comparing effectiveness of beta blocker-metoprolol; a specific If blocker-ivabradine and its combination in patients who develop IST as a complication following CABG.
MATERIALS AND METHODS: An open-labeled, investigator initiated, clinical study was conducted on 150 patients who developed IST (heart rate [HR] >100 beats/min) following elective CABG surgery. The patients were randomized into three treatment groups. Group I - received ivabradine (5 mg), Group II - metoprolol (25 mg), and Group III - ivabradine (5 mg) and metoprolol (25 mg). Treatment was given orally, twice a day for 7 days in all the three groups postoperatively. Primary endpoints were comparative effectiveness in HR and blood pressure reduction following treatment.
RESULTS: IST was diagnosed by an electrocardiogram (12-lead) considering morphological features of P-wave and with 32% increase from baseline HR in all the three groups. Compared to IST arrthymic rate, HR was reduced in all groups following respective treatment (P = 0.05). Reduction in HR was significant (P < 0.05) in combination group followed by ivabradine which was significantly greater than metoprolol treated group. None of the treatments clinically changed the systolic, diastolic and mean blood pressure till discharge. No surgery/treatment-related complications were observed in any groups.
CONCLUSION: Ivabradine stands as a pharmacological option for controlling HR and rhythm without associated side effects in postoperative CABG patients with IST.

Introduction

In patients with coronary artery disease (CAD), very commonly coronary artery bypass graft (CABG) surgeries are performed.[1] Arrhythmias stands as a common complication arising due to CABG.[2] Inappropriate sinus tachycardia (IST) heart rate (HR) >100 bpm is a common arrhythmic complication of CABG surgery. IST is diagnosed on the basis of persistent or recurrent sinus tachycardia on an electrocardiogram considering P-wave morphological features, similar to normal sinus rhythm. If untreated, increases the incidence of postoperative stroke.[12]

Explanatory mechanisms for IST are complex and multi-factorial, amounting to dysautonomia, a problem of intrinsic sinus node problem or multiple factors.[3] Pathophysiology of IST is complex and poorly understood. The mechanisms include excessive and reduced sympathetic and parasympathetic activity respectively, ectopic sinus node activity; increased intrinsic HR, and influence of β-receptor antibodies.[4] Irrespective of the influencing mechanism(s) abnormally higher activation of the pacemaker If current stands as the common cause. This ionic If current generates sinoatrial node diastolic depolarization spontaneously.[5]

β-adrenergic antagonists have been investigated in patients with IST. Although effective are associated with wide range of cardiovascular actions and effects on multiple body systems. This limitation of β-adrenergic antagonists complicates the interpretation of reduction in HR as well its associated intolerable side effects.[6] Recently introduced ivabradine, is a specific If blocker which does not interact with the cardiovascular system, thus providing a unique opportunity to study the effect of total If blockade on HR and IST associated variable symptoms.[7] Cardioprotective effects of ivabradine in CAD patients (HR at rest ≥70 b.p.m) associated with or without left ventricular systolic dysfunction, was evaluated by the BEAUTIFUL and SIGNFY studies.[18] An overall cardioprotective benefit was reported in neither study; BEAUTIFUL study analysis among post hoc patients with symptom-limiting angina showed 42% reduction in myocardial infarct hospitalizations.[91011] Thus, in the SIGNIFY study, a subgroup analysis (CCS Class II–IV angina) was undertaken.[12] According to both studies, with confidence at lower contemporary clinical doses (5–7.5 mg bid.) ivabradine can be used for the treatment of angina.[8] As per SHIFT report the reduction in HR by beta-blocker in combination with ivabradine, rather than beta-blocker alone is primarily responsible for the outcomes.[111213] Thus, these findings remain inconclusive to the use, recommended dose or combination treatment of ivabradine; more so in CABG patients with IST. Thus, the objective was primarily to compare the safety and efficacy of metoprolol (25 mg bid), ivabradine (5 mg bid) and their combination-metoprolol (25 mg) and ivabradine (5 mg) bid administered for 7 days to patients who developed IST following CABG. Reduction in blood pressure and HR after treatment were the measured endpoints.

Materials and Methods

An open-labeled, investigator initiated randomized, clinical study was conducted at a tertiary care group cardiology practice center between January 1, 2017 and March 2018. With an average between 50 and 75 CABG surgeries performed per month at the center and a prevalence of 30%–40% IST in CABG patients, a sample size of 150 patients who underwent elective CABG and developed IST (HR >100 beats/min) following surgery were consented and randomized to three treatment groups.

Group I – Ivabradine 5 mg (b.i.d, n = 50)

Group II – Metoprolol 25 mg (b.i.d, n = 50)

Group III – Ivabradine 5 mg + Metoprolol 25 mg (b.i.d, n = 50).

CABG surgery and treatment of the patients were as per the standard protocol placed by the American College of Cardiology/American Heart Association (AHA/ACC) guidelines.[1] Patients not eligible for the study included those with atrioventricular block (2° and 3°), bradycardia (HR <50 beats/min), heart failure (New York Heart Association Class IV). Patients with cardiogenic shock and pulmonary disease were also excluded. Patients with known hypersensitivity to beta-antagonists or ivabradine; participant to another clinical trial, unable to follow-up or comply with the hospital protocol were also not included. Occurrence of adverse events such as reduction in HR, gastrointestinal distress, skin reactions, and cold extremities was considered as study drop out criteria. The Institutional Ethics Committee reviewed and approved the study protocol (# EC/O-472). A written informed consent was given by the study participants.

Postoperatively, treatment was given for 7 days in all the three groups, and the patients were followed-up till discharge. All study participants were administered the same brand of Ivabradine (Ivabrad) or Metoprolol (Betaloc) orally throughout the study period.

Cardiac rhythm, HR, blood pressure (mean, systolic, and diastolic), hemoglobin, temperature, and central venus pressure (CVP) were measured at the time of drug administration, at 3, 6, 12, 18, 24, 36, 48, and 72 h and at intensive care unit (ICU) discharge.

Study endpoints were composite effectiveness and safety endpoint in terms of reduction in blood pressure and HR; in-hospital mortality and occurrence of atrial fibrillation/arrhythmias, atrioventricular block (3°), implanting a pacemaker, worsening heart failure and symptomatic subjective self-reporting of quality of life (QoL).

Statistical analyses

Continuous and categorical variables are presented as mean ± standard deviation and as percent, respectively. All dependent variables were analyzed by the two-way ANOVA with repeated-measured Bonferroni's multiple comparison test. A two-sided P < 0.05 defines the statistical significance. Statistical analysis was performed using the Graph Pad Prizm 6 software (Version 6.02) (Version 6.02 )San Diego, CA 92108, US.

Results

Among 180 patients diagnosed with IST, 150 were randomized, whereas 30 patients were excluded based on the exclusion criteria. Each group included 50 participants who were diagnosed with IST (persistent or recurrent sinus tachycardia) on electrocardiogram recordings considering P-wave morphological features. Intraoperative conditions were similar in all groups. Most of the patients (97.77%) were operated through “Off pump” CABG. The study adhered to the CONSORT statement for enrolment, treatment allocation, follow-up, and data analysis of study participants. Baseline characteristics and preoperative conditions were well balanced among all the groups with a propensity score of 0.8, as depicted in Table 1.

Table 1

Baseline and preoperative characteristics

Variables	Ivabradine (n=50)	Metoprolol (n=50)	Ivabradine + metoprolol (n=50)
Age (years)	59.46±8.8211	59.33±8.3618	59.25±8.5521
Weight (kg)	70.28±11.4984	68.14±12.2118	68.43±11.4930
Height (cm)	165.25±8.3921	163.46±9.1456	164.05±7.4593
BMI (kg/m2)	25.69±3.4065	25.55±4.30	25.45±4.0899
Heart rate (bpm)	80.61±13.2461	77.53±9.6593	80.70±11.0366
Systolic BP (mm Hg)	123.18±12.417	126.01±15.361	122.95±18.3980
Diastolic BP (mm Hg)	80±10.3235	78.51±8.8192	76.81±10.6603
Respiration rate (breath/min)	21.6±2.1487	21.41±3.1477	21.15±1.9382
Temperature (Fahrenheit)	98.42±0.3010	98.44±0.243	98.48±0.2677

BMI=Body mass index, BP=Blood pressure

Effect on heart rate

IST developed post-CABG, averaging to 108 ± 5.2 beats/min among the three groups following CABG in the ICU; 32% increase from baseline HR in the subjects. Significant reduction in HR (P < 0.001) was noted in all the groups following respective treatment [Figure 1]. Comparing among treatment groups, reduction in HR was significantly (P < 0.05) greater in ivabradine (5 mg) + metoprolol (25 mg) group followed by ivabradine (5 mg) group wherein reduction in HR was greater than metoprolol (25 mg) treated group. At 18 h, combination treatment reduced 20% HR, ivabradine 15% while metoprolol 13% reduction; at 36 h' combination treatment reduced 26%, ivabradine 22% and metoprolol reduced 16% HR; at 72 h' combination versus ivabradine versus metoprolol produced 30% versus 26% versus 21% reduction in HR, respectively. At discharge from ICU, normal sinus rhythm (HR: 76 ± 4.2 beats/min) was attained in all groups. Figure 1 depicts comparative HR at different time intervals in different groups; FNx01 presents statistical significance at P < 0.001 in comparison to metoprolol group while † presents statistical significance at P < 0.05 in comparison with ivabradine treatment group.

Figure 1

Ivabradine + Metoprolol

Effect on blood pressure

In ICU systolic, diastolic and mean blood pressure were within the normal range in all the three treatment groups which averaged to 123.88 ± 1.22, 76 ± 1.21, 92.3 ± 1.6 mm Hg, respectively. None of the treatments clinically changed the systolic, diastolic, and mean blood pressure till discharge. Table 2 compares the reduction in blood pressure in the treatment groups. Although reduction in systolic, diastolic, and mean blood pressure was the highest in combination group (P < 0.05) followed by metoprolol group, followed by ivabradine group the reduction was not clinically significant [Figures 2 and 3]. Figures 2 and 3 compare systolic and diastolic blood pressure, respectively, among the three groups, whereinFNx01 presents statistical significance at P < 0.001 in comparison to metoprolol group while † presents statistical significance at P < 0.05 in comparison to Ivabradine-treated group.

Table 2

Comparison of reduction in blood pressure in the treatment groups

Percentage reduction in blood pressure (mm Hg)	Ivabradine (n=50)	Metoprolol (n=50)	Ivabradine + metoprolol (n=50)
Systolic	0.2	3.3	7.06*
Diastolic	0.76	0	4.31*
Mean	0.52	1.41	5.37*

*Statistical significance at p<0.05 in comparison to ivabradine and metoprolol

Figure 2

Comparison of systolic blood pressure at different time intervals in different groups

Figure 3

Comparison of diastolic blood pressure at different time intervals in different groups

Effect on body temperature, pain score, and hemoglobin level at discharge from the intensive care unit

During ICU stay, there was no significant (P > 0.05) change in the body temperature in the treatment groups. Body temperature was normal (97.2 ° F) and similar postoperatively across all treatment groups. No significant (P > 0.05) difference in pain score of the patients in each treatment group was observed which averaged to 0.05 during ICU discharge. CVP at 12 h following surgery averaged to 3.44 and was similar in all treatment groups. Estimation of hemoglobin depicted nearly normal values similar in all treatment groups averaging to 11.23 (data not shown). Thus, on discharge from ICU-body temperature, pain score and hemoglobin levels were similar and normal in all treatment groups.

Duration of intensive care unit and hospital stay

No significant (P > 0.05) difference was observed in ICU and total hospital stay in all treatment groups. The duration of ICU stay averaged to 3.7 ± 0.5 days while total hospital stay averaged to 7.3 ± 1.2 days which was statistically similar among groups [Table 3].

Table 3

Duration of the intensive care unit and hospital stay

Hospital stay (days)	Ivabradine (n=50)	Metoprolol (n=50)	Ivabradine + metoprolol (n=50)
ICU	3.5±0.05	3.7±0.1	3.8±0.1
Total duration of stay	7.3±0.05	7.3±0.05	7.4±0.05

ICU=Intensive care unit

Subjective self-reporting and safety endpoints

None of the study participants subjectively reported palpitation, dyspnea, or fatigue affecting their QoL. No in-hospital mortality was reported. Surgery-related complications such as atrial fibrillation/arrhythmias, atrioventricular block (third degree), and use of temporary pacemaker or worsening heart failure did not occur in any groups.

Discussion

In our knowledge, this is the first study assessing and comparing the safety and efficacy of ivabradine and metoprolol alone and its combination for preventing IST among CABG patients. IST is a common complication with a prevalence of 30%–40% which occurs after cardiac surgery resulting in longer stays in ICU's and hospital; a two to three-fold higher risk of stroke and delirium postoperatively and neurocognitive decline.[1415161718] Incapacitating symptoms such as light headedness, dizziness, dyspnea, palpitations, and syncope postoperatively are associated with IST. Before surgery, withdrawal of beta-blockers should be avoided since it increases the risk of atrial fibrillation postoperatively.[14] The prevalence of IST after surgery increases the incidence of morbidity and mortality; besides longer hospitalizations leading to an economic burden. Thus, the prevention of IST is increasingly important.[19]

ACC/AHA 2004 and European Society of Cardiology guidelines recommend the postoperative use of beta-blockers (Class I evidence) for the prevention of atrial fibrillation in those patients who are not contraindicated beta-blocker therapy.[14] Beta-antagonists such as propranolol, atenolol, metoprolol, acebutolol, timolol, carvedilol, and betaxolol have been studied to prevent atrial fibrillation following cardiac surgery.[19202122232425] Beta-blockers along with reduction in HR tend to reduce blood pressure which could stand as a disadvantage in many cases. Ivabradine is a specific inhibitor of sinoatrial If current thereby contributing to reduced HR without affecting blood pressure, intracardiac conduction, ventricular repolarization, or myocardial contractility.

According to BEAUTIFUL clinical study, ivabradine in a subgroup of patients (baseline HR ≥70 beats/min.) reduced the incidence of endpoints related to CAD (hospital admission for acute myocardial infarction) reporting it to be safe in CAD patients with impaired left-ventricular function (systolic), along with beta-blockers.[3] Furthermore, β blocker and ivabradine together improved CAD outcomes in patients with tachycardia (HR >70 bpm) suggesting beneficial effects of lower HR on CAD outcomes.[3] The SHIFT trial was conducted in stable patients with symptomatic chronic heart failure with left ventricular ejection fraction ≤35% and resting HR ≥70 bpm.[13] In this study, adding ivabradine to standard of care reduced heart failure associated risks like hospital admission or death associated with worsening heart failure significantly.[13] Based on these studies, it can be inferred that ivabradine improves clinical outcomes due to reduction in HR in CABG patients which have associated systolic left ventricular dysfunction or heart failure.

In the present study, postoperative prevention of inappropriate sinus tachyarrhythmias in the combined therapy (ivabradine [5 mg] plus metoprolol [25 mg]) group was more effective than either metoprolol or ivabradine given alone. However, this postoperative reduction of HR was associated with a slight blood pressure reduction also.

Instead of standardized quality-of-life tools, semi-quantitative EHRA classification based subjective self-reporting symptoms by patients was used.[26] The checked symptoms included palpitation, dyspnea, fatigue, hypotension, bradycardia, or requiring implantation of pacemaker. No in-hospital mortality, occurrence of atrial fibrillation/arrhythmias, atrioventricular block (3° block), need for pacemaker, worsening heart failure was observed in any treatment groups. No significant difference in ICU or hospital stay was noted among treatment groups since hospital protocols were followed for CABG surgery.

With respect to the composite effectiveness more so in relation to reduction of HR without associated hypotension ivabradine and its combination with metoprolol were superior to metoprolol alone.

Study limitations

Nearly 85% of the study participants were on beta-blockers preoperatively. As per the institutional protocol, this treatment with beta-blockers was not discontinued prior to randomization. Thus, the absence of wash out period was a study limitation. Furthermore, the number of study participants was of a single center and small in number in each group. This limitation can be addressed by conducting a multicenter randomized control study with a larger study population.

Conclusion

In patients undergoing CABG with contraindications to beta-blockers, ivabradine stands as a pharmacological agent for controlling HR and rhythm when given early in the postsurgical period. Ivabradine improves sinus rhythm without influencing blood pressure postoperatively after CABG in patients with IST without any other side effects. Combination of ivabradine and metoprolol improves sinus rhythm and rate in the early postsurgical period in patients undergoing CABG patients with no contraindications to beta-blockers. The combination may be recommended for patients with hypertension, although the outcomes of large randomized control trials would be required to confirm the same.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.