Maintenance of sinus rhythm after electrical cardioversion of persistent atrial fibrillation

Design

Prospective, randomized, open-label study

N= 128

Objective

To compare the efficacy and safety of sotalol and bisoprolol in the maintenance of sinus rhythm after electrical cardioversion of atrial fibrillation

Study Groups

Bisoprolol (n= 64)

Sotalol (n= 64)

Inclusion Criteria

Electrocardiogram (ECG)-documented persistent atrial fibrillation (lasting more than 2 weeks) and successful electrical cardioversion to sinus rhythm

Exclusion Criteria

Prior treatment with study medication for maintenance of sinus rhythm; any contraindications to beta-blockers; prolonged QT interval (QT > 480 ms, QTc > 400 ms); sinus bradycardia < 45 beats/min; concomitant administration of drugs capable of repolarization

Methods

Immediately after successful electrical cardioversion, patients were randomized to receive bisoprolol 5 mg/day or sotalol 80 mg BID orally. All patients received ECG monitoring in the hospital for at least 24 hours post-cardioversion. Heart rate, PQ, QRS, and QT intervals were evaluated using a 12-lead ECG 1 day and 1 month after successful cardioversion and at 3 monthly intervals thereafter. Study medication was withheld in cases of symptomatic bradycardia (heart rate < 45 beats/min) or any high-degree conduction disturbance, a prolonged QT interval of > 480ms or a corrected QT interval of > 400 ms, in proarrhythmias (e.g., torsades de pointes) or symptomatic hypotension (systolic blood pressure < 90 mmHg).

Duration

Follow-up: 1 year

Outcome Measures

Recurrence of persistent atrial fibrillation, ECG values

Baseline Characteristics

Sotalol (n= 64)

Age, years

Male, n

Weight, kg

Left atrial diameter, mm

Left ventricular ejection fraction, %

Duration of atrial fibrillation before study entry, months

Underlying heart disease, n

No evidence of underlying heart disease

Coronary artery disease

Hypertension

Cardiomyopathy

Valve disease

10

23

21

6

4

16

22

19

3

4

ECG values

Heart rate, beats/min

QRS, ms

QT, ms

QTc, ms

66

88

370

389

66

90

375

392

Results

Endpoint

Bisoprolol (n= 60)

Sotalol (n= 56)

p-value

Recurrence of atrial fibrillation

Monthly relapse rate

Time of relapse after cardioversion, days

Recurrence within the first month

25 (42%)

3.5%

38 ± 74

65%

23 (41%)

3.4%

49 ± 87

70%

-

Not significant

Not significant

Not significant

ECG values at day 30

Heart rate, beats/min

QRS, ms

QT, ms

QTc, ms

66 ± 9*

92 ± 18

381 ± 30

407 ± 30

59 ± 7*

94 ± 22

425 ± 37*

428 ± 37*

Not significant

Not significant

< 0.001

Not significant

Efficacy analysis was feasible in 116 patients, 56 of whom were randomized to sotalol and 60 to bisoprolol, respectively, due to withdrawal due to adverse events and non-compliance (three on sotalol, two on bisoprolol).

*p< 0.001 vs. baseline

Adverse Events

Common Adverse Events: N/A

Serious Adverse Events: See below

Percentage that Discontinued due to Adverse Events: Three patients (4.6%) in the bisoprolol group were withdrawn versus 4 (6.3%) patients in the sotalol group. Patients were withdrawn for sinus bradycardia (one on sotalol, three on bisoprolol), torsades de pointes tachycardias (two on sotalol), prolonged QT interval with bradycardia (one on sotalol).

Study Author Conclusions

This study demonstrates that sotalol (160 mg/day) and bisoprolol (5 mg/day) are equally effective in maintaining sinus rhythm. Because of the side effects of sotalol, bisoprolol seems to be advantageous for maintenance of sinus rhythm after cardioversion of atrial fibrillation.

InpharmD Researcher Critique

Summary Table of Bisoprolol Comparison to other Beta Blockers (BB)

Choi et al., 2019¹

Prospective, multicenter, cohort study

N= 3,016 (Korea)

BB at discharge (n= 1,707)

Carvedilol prescription (n= 831)

Bisoprolol prescription (n= 553)

No BB at discharge (n= 1,309)

Patients with HFrEF; hospitalized for AHF

Excluded patients on very low dose BB (standardized dose of carvedilol ≤ 3.125 mg) or other types of BB

Relevant data extracted from the Korean Acute Heart Failure (KorAHF) registry

Median follow-up duration: 28 months (IQR 18 to 37)

Mean daily doses: 11.5 ± 8.9 mg carvedilol vs 2.3 ± 1.6 mg bisoprolol

Rate of all-cause mortality: 27.5% vs. 23.5% (HR 1.21; 95% CI 0.99 to 1.47; p= 0.07)

Adjusted HR: 1.22; 95% CI 0.98 to 1.52; p= 0.07

Proportion of maintenance of BB: 71.7% vs. 74.9%; p= 0.23

Author's conclusion: In the treatment of AHF with reduced EF after hospitalization, the mortality benefits of carvedilol and bisoprolol were comparable in AHF patients with HFrEF.

Hori et al., 2014²

Prospective, randomized, double-blind, active-controlled, multicenter, parallel-group study

N= 59 (Japan)

Bisoprolol (n= 31)

Carvedilol (n= 28)

Stable CHF patients caused by ischemic heart disease or dilated cardiomyopathy

Duration: 36 weeks

Randomly assigned to either bisoprolol or carvedilol; both given orally twice daily

Bisoprolol started at a dose of 0.625 mg/day (Step 1); increased stepwise to 1.25 mg/day (Step 2), 2.5 mg/day (Step 3), 3.75 mg/day (Step 4), and 5 mg/day (Step 5) until Week 16

Carvedilol started at 2.5 mg/day (Step 1); increased to 5 mg/day (Step 2), 10 mg/day (Step 3), and 20 mg/day (Steps 4 and 5).

Thereafter, patients maintained the highest dose level achieved

Mean maintenance doses: 3.3 mg/day bisoprolol vs. 13.6 mg/day carvedilol

Mean durations of treatment: 188.2 days vs. 172.9 days

Changes from baseline to Week 32:

• LV EF: 11.7 ± 8.6% vs. 10.1 ± 10.5%; p= 0.342
• LV end-diastolic volume: -37.5 ± 48.7 mL vs. -24.7 ± 29.4 mL; p= 0.132
• LV end-systolic volume: -41.9 ± 43.0 mL vs. -29.3 ± 25.9 mL; p= 0.098

Cumulative event-free rate for a composite of cardiovascular (CV) death or admissions to hospital for worsening CHF: 92.4% vs. 94.7%

Author's conclusion: Bisoprolol, at half the dose used in other countries, is well tolerated and is as effective as carvedilol for treating Japanese patients with mild to moderate CHF.

Fröhlich et al., 2017

Matched-cohort study

N= 6,010 (Norway, Germany, England)

Bisoprolol (n= 1,023)

Carvedilol (n= 1,721)

Metoprolol succinate (n= 3,266)

Outpatients with stable CHF; LVEF < 45%; prescribed either bisoprolol, carvedilol, or metoprolol succinate

Daily doses of 10 mg bisoprolol or 50 mg carvedilol were considered 100% dose equivalent, while 5 mg bisoprolol and 25 mg carvedilol were defined as 50% dose equivalent.

Patients were individually matched with respect to both dose equivalents and the respective propensity scores for BB treatment.

Bisoprolol and carvedilol were associated with lower mortality than metoprolol succinate (HR 0.80, 95% CI 0.71–0.91, p< 0.01, and HR 0.86, 95% CI 0.78–0.94, p< 0.01, respectively).

Bisoprolol or carvedilol had similar mortality (HR 0.94, 95% CI 0.82–1.08, p= 0.37).

No significant association between BB choice and all-cause mortality in any of the matched samples (HR 0.90; 95% CI 0.76–1.06; p= 0.20; HR 1.10, 95% CI 0.93–1.31, p= 0.24; and HR 1.08, 95% CI 0.95–1.22, p= 0.26 for bisoprolol vs. carvedilol, bisoprolol vs. metoprolol succinate, and carvedilol vs. metoprolol succinate, respectively).  

Author's conclusion: Our results suggest that the three beta-blockers investigated have similar effects on mortality amongst patients with CHF.

Perreault et al., 2017

N= 3,197 (Canada)

Metoprolol (n= 1,869)

Carvedilol (n= 302)

Bisoprolol (n= 1,026)

Patients aged 66 years or older; hospital admission with a primary diagnosis of HF (not within 3 years prior to study); BB filled within 30 days of the hospital discharge

Relevant data extracted from Quebec government’s administrative database of hospital discharges (Med-Echo) and databases of Quebec medical services and Quebec’s public drug plan

Patients characterized by the type of BB prescribed at discharge of their first HF hospitalization.

Target doses of evidence-based BB 3 and 6 months after initiation were defined as 50 mg/day for carvedilol, 200 mg/day for metoprolol succinate, and 10 mg/day for bisoprolol.

Median follow-up: 2.8 years

Crude annual mortality rates (per 100 person-years): 16 metoprolol tartrate vs. 14.9 carvedilol vs. 17.7 bisoprolol; adjusted HRs of carvedilol (HR 0.92; 0.78–1.09) and bisoprolol (HR 1.04; 0.93–1.16) were insignificant compared to metoprolol tartrate (HR 1 [reference]) in all-cause mortality rate.

After matching for propensity score, carvedilol and bisoprolol showed no additional benefit with respect to all-cause mortality compared with metoprolol tartrate.

Author's conclusion: Our evidence suggests no differential effect of BB on all-cause mortality among older adults with HF

Düngen et al., 2011⁵

Randomized, double-blind, parallel-group trial (CIBIS-ELD)

N= 883 (Europe)

Bisoprolol (n= 431)

Carvedilol (n= 445)

Age ≥ 65 years with symptomatic chronic heart failure consistent with New York Heart Association functional class ≥ II or LVEF ≤ 45%

Initial titration phase: dose scheduled to double at every visit to reach the target dose of 10 mg bisoprolol once daily or 25 mg carvedilol twice daily within 6 weeks (50 mg twice daily within 8 weeks for patients > 85 kg)

Maintenance period: 4 weeks

Tolerability: 24% bisoprolol vs. 25% carvedilol (p= 0.64)

Reduction of heart rate: −8.4 (95% CI −9.8 to −7.0) vs. −6.0 (95% CI −7.2 to −4.7); mean adjusted difference -2.1 beats/minute (95% CI -3.6 to -0.5); p= 0.008

Dose-limiting bradycardic adverse events: 16% vs. 11% (p= 0.02)

Reduction in forced expiratory volume: +3 (−32 to +39) vs. −42 (−73 to −11); mean adjusted difference +50 mL (+4 to +95); p= 0.03

Author's conclusion: Overall tolerability to target doses was comparable. The pattern of intolerance, however, was different: bradycardia occurred more often in the bisoprolol group, whereas pulmonary adverse events occurred more often in the carvedilol group.

AHF, acute heart failure; BB, beta-blocker; CHF, congestive heart failure; CI, confidence interval; EF, ejection fract; HFrEF, heart failure with reduced ejection fraction; HR, hazard ratio; IQR, interquartile range; LV, left ventricular

Effectiveness of bisoprolol versus other β-blockers and other antihypertensive classes: a cohort study in the Clinical Practice Research Datalink

Design

Non-interventional, retrospective, cohort study

N= 26,352

Objective

To compare blood pressure (BP) and safety outcomes in patients with hypertension initiating bisoprolol, versus other β-blockers

Study Groups

Bisoprolol (n= 1,327)

Other β-blockers (n= 5,308)

Inclusion Criteria

Age ≥ 18 years, in the UK Clinical Practice Research Datalink (CPRD) database, newly initiated monotherapy with an antihypertensive drug, no record of being prescribed any antihypertensive drugs in the prior year, first diagnosis for hypertension in the prior 6 months and at least 1 year of prior medical history, no record of any antihypertensive drugs other than the index drug for 14 days after the index date

Exclusion Criteria

Not explicitly stated

Methods

For the purpose of this table, only data pertaining to the comparison of bisoprolol and other β-blockers were included. Data were extracted from CPRD, a primary care database that collects anonymized electronic patient medical records from general practitioners in the UK.

Patients were allocated to treatment cohorts based on the antihypertensive monotherapy initiated at the index date. The bisoprolol cohort consisted exclusively of patients who received bisoprolol as monotherapy, whereas the 'other β-blockers' cohort included any other β-blocker monotherapy including acebutolol, atenolol, betaxolol, carteolol, carvedilol, celiprolol, labetalol, metoprolol, nadolol, nebivolol, oxprenolol, pindolol, propranolol, or timolol. Patients initiating bisoprolol were matched with up to four patients in the cohort of patients receiving other β-blockers.

Patients were followed from the index date (date of first prescription) plus 1 day, until the first occurrence of any of the following events: addition of another antihypertensive drug to the index treatment, discontinuation of the index treatment, patient death, transfer-out date or the end of the study period.

Duration

Initiated β-blocker between January 1, 2000 and December 31, 2017

Average follow-up: 23.3 months for bisoprolol and 20.2 months for other β-blockers

Outcome Measures

Primary: average variation of systolic blood pressure (SBP) and diastolic blood pressure (DBP)

Secondary: controlled BP state (SBP < 140 mmHg or DBP < 90 mmHg) and uncontrolled BP state; first occurrence of type 2 diabetes mellitus (T2DM), dyslipidemia, erectile dysfunction, or obesity

Baseline Characteristics

Bisoprolol (n= 1,327)

Other β-blockers (n= 5,308)

Age, years*

Male

Body-mass index, kg/m^2*

Blood pressure, mmHg*

Systolic

Diastolic

163

96

160

95

*Median values

Results

The linear mixed model propensity score-matched coefficient (98.75% confidence interval [CI]) for average variation of blood pressure for bisoprolol versus other β-blockers was 1.20 mmHg (-0.01 to 2.40) for SBP and 0.46 mmHg (-0.18 to 1.11) for DBP, resulting in a nonsignificant propensity score-matched HR between controlled and uncontrolled blood pressures of 0.97 (98.75% CI 0.89 to 1.05).

There was no difference in the risk of developing T2DM, dyslipidemia, obesity, or erectile dysfunction between bisoprolol and other β-blockers.

Adverse Events

Common Adverse Events: Not disclosed

Serious Adverse Events: Not disclosed

Percentage that Discontinued due to Adverse Events: N/A

Study Author Conclusions

Overall, this study adds real-world support to the evidence gathered from several RCTs that no difference is observed in a term of BP decrease between the major antihypertensive classes. This study has not shown any difference between bisoprolol and other antihypertensive classes, in terms of risk of T2DM, obesity or erectile dysfunction, but an increased risk of dyslipidemia only in the comparison with diuretics. These data support further consideration of the use of bisoprolol for the treatment of patients with hypertension.

InpharmD Researcher Critique