Abstract
Background
Traditionally, amiodarone or electrical cardioversion was used if radiofrequency catheter ablation (RFCA) could not terminate atrial fibrillation during the procedure in patients with persistent atrial fibrillation (PeAF).
Objective
To investigate whether the nifekalant instead of amiodarone during RFCA improve procedure outcomes in patients with PeAF.
Methods
This study enrolled patients with PeAF who failed to achieve cardioversion after initial ablation at our center between January 2020 and December 2022. These patients were classified into the nifekalant (N) group and the amiodarone (A) group. And patients were followed for 1 year to evaluate long-term success rates. Subgroup analyses and the logistic regression analyses were performed.
Results
The study comprised 300 participants and included N (n = 121) and A (n = 179) groups. Following propensity score matching (PSM), 101 participants were in each group. Within the N and A groups, 57(56.44 %) and 19(18.81 %) cases successfully terminated AF, 45 (44.56 %) and 15(14.85 %) cases achieved conversion to atrial tachycardia (P < 0.001), respectively. The ventricular tachycardia was observed in only one case in the N group (P > 0.05). The follow-up results demonstrated that one-year success rates were 63.37 % and 49.50 % for the N and A groups (P < 0.05).
Conclusion
For patients with PeAF that persists after initial catheter ablation, compared to amiodarone, administration of nifekalant could convert atrial fibrillation into atrial tachycardia, following by target ablation, has the potential to improve the procedure outcomes.
Keywords: Nifekalant, Amiodarone, Persistent atrial fibrillation, Radiofrequency catheter ablation
1. Introduction
Atrial fibrillation (AF) represents one of the most prevalent clinical tachyarrhythmias, its risk escalating with age[1]. Transcatheter radiofrequency ablation currently serves as a pivotal treatment modality for AF, demonstrating notable efficacy, especially in managing paroxysmal AF[2], [3]. And in cases of PeAF, the long-term efficacy of catheter ablation is elevated in recent years, nevertheless, yielding unsatisfactory outcomes[4]. Consequently, augmenting the success rates of catheter ablation for PeAF holds paramount importance.
The RFCA procedure for PeAF typically begins with bilateral pulmonary vein isolation[5]. Some centers may add linear ablation, while a few map the atrial matrix and perform necessary matrix modifications after electrical cardioversion [4], [5], [6]. Currently, regarding catheter ablation of patients with PeAF, amiodarone or electrical cardioversion is often used to restore sinus rhythm if the initial ablation failed to convert the AF in many centers.
It is known that Nifekalant is a fast-acting class III antiarrhythmic drug, which has a faster onset of action and shorter half-life compared to amiodarone, without inducing negative inotropic effects and also reducing cardiac function[7], [8]. Moreover, nifekalant demonstrated a significant reduction in the defibrillation threshold among patients with AF, resulting in facilitating electrical cardioversion of AF [9], [10]. However, research on the efficacy of nifekalant on PeAF during RFCA is still limited. Recently, we have found that the administration of low-dose nifekalant seems to be able to convert more patients into atrial tachycardia and further target ablation could restore sinus rhythm.
Here, we investigate whether the nifekalant instead of amiodarone can improve procedure outcomes in patients with PeAF undergone radiofrequency ablation.
2. Materials and Methods
2.1. Study population
The study was approved by the Ethics Committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, −Wuhan, −Hubei Province.
A retrospective analysis was performed on 300 patients with PeAF who underwent unsuccessful RFCA at the Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology between January 2020 and December 2022. Inclusion criteria: (1) Electrocardiogram confirmed AF, lasting ≥ 7 days; (2) Signed informed consent, chose percutaneous RFCA, with antiarrhythmic and electrical cardioversion used as necessary; (3) Q-T interval < 0.5 s; (4) Patients without left atrial thrombosis on preoperative transesophageal echocardiography; Exclusion criteria: (1) Patients with acute pulmonary edema, acute hemorrhagic/ischemic stroke or other conditions contraindicating surgical treatment; (2) Patients with significant sinus bradycardia (sick sinus syndrome); (3) Patients with severe bleeding tendency; (4) Patients with severe liver and kidney dysfunction; (5) Severe infection and other late-stage chronic wasting diseases.
2.2. Study protocol
All patients were divided into N and A groups based on the intraoperative use of nifekalant or amiodarone. The baseline data were collected: gender, age, height, weight, body mass index, past medical history (smoking history, hypertension, diabetes, cerebral infarction, coronary heart disease), course of AF, left atrial end-diastolic diameter, left ventricular ejection fraction, Q-T/QTc interval before medication, QRS wave width. Observing the outcomes of the two groups after medication, the Q-T/QTc interval, QRS wave width, and adverse events (significant prolongation of Q-T interval, VT, VF, hypotension) were recorded respectively. Following surgery, antiarrhythmic therapy is performed regularly according to the guidelines. And follow-up was conducted at 3, 6, and 12 months after ablation, which included assessing relevant symptoms by phone and regularly performing 12-lead ECG and 24-hour Holter monitoring to evaluate the recurrence of AF, defined as any episodes of atrial arrhythmias lasting at least 30 s after a three-month blanking period[11].
2.3. Procedure and drug cardioversion
All patients signed informed consent of procedure and using medication or electrical cardioversion if necessary, and be aware of relevant risk before procedure. All patients were required to complete transesophageal echocardiography before procedure to rule out thrombosis in the left atrium or left atrial appendage. Fasting for 6–8 h before procedure, supplementing energy and electrolytes appropriately to maintain the patient's body needs.
RFCA was performed on patients with PeAF under the guidance of a three-dimensional electroanatomic mapping system. The vital signs of the patients were closely monitored during the procedure. After bilateral pulmonary vein isolation, patients who were still in AF were divided into the N and A group. This step was mainly determined by the surgeon. Under continuous electrocardiographic monitoring, nifekalant (0.3 mg/kg)[12] and amiodarone (5 mg/kg)[13] were given intravenously for drug cardioversion. The injection was completed within 5–20 min, and observed until 20 min after administration. If the patients converted to atrial tachycardia or sinus rhythm during the observation period, it was considered an effective drug therapy, and target ablation was performed after positioning. On the contrary, it was considered less effective, and the electrical cardioversion was used to conclude the procedure after intravenous anesthesia.
2.4. Statistical analysis
Statistical analysis was performed using R and SPSS26.0. PSM was performed to match the two groups 1:1 to control confounding factors. The data after PSM were subjected to subsequent analysis. Continuous data were presented as mean ± standard deviation (Mean ± SD) or median, interquartile range [M (Q1, Q3)], and were analyzed using t-test or Mann-Whitney test. Categorical data were presented as number, percentage [n (%)], and were analyzed using chi-square test or Fisher's exact test. Subgroup analyses included age strata and sex etc. Logistic regression analysis was used to identify independent risk factors for recurrence in patients. The results were expressed as odds ratios (OR) and corresponding 95 % confidence intervals (CI).
3. Results
3.1. Baseline characteristics
A total of 300 eligible patients were enrolled in this study, with 121 in the N group and 179 in the A group. All baseline characteristics of the patients were used for PSM, including sex, age, height, weight, BMI, medical history, duration of AF, echocardiographic and ECG-related indicators; each group included 101 patients after matching. The baseline characteristics of the two groups were uneven before matching, but showed no statistically significant differences after matching (P > 0.05). The mean age of the N group was 61.00 (56.50, 69.00) years, of which 76.24 % were male; while the mean age of the A group was 62.00 (55.00, 67.50) years, of which 71.29 % were male (Table 1).
Table 1.
Comparison of general baseline characteristics.
| Variable | Before PSM |
After PSM |
|||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Total (n = 300) | N (n = 121) | A (n = 179) | Statistic | P | SMD | Total (n = 202) | N (n = 101) | A (n = 101) | Statistic | P | SMD | ||
| Age, M (Q1, Q3) | 61.00 (56.00, 68.25) | 61.00 (57.00, 69.00) | 62.00 (55.00, 68.00) | Z = -0.343 | 0.732 | −0.047 | 61.00 (56.00, 68.00) | 61.00 (56.50, 69.00) | 62.00 (55.00, 67.50) | Z = -0.713 | 0.476 | −0.124 | |
| Height, M (Q1, Q3) | 170.00 (163.00, 175.00) | 170.00 (165.00, 175.00) | 168.00 (162.00, 174.00) | Z = -2.338 | 0.019 | −0.298 | 170.00 (164.00, 175.00) | 170.00 (165.00, 175.00) | 169.00 (163.00, 174.00) | Z = -1.366 | 0.172 | −0.208 | |
| Weight, M (Q1, Q3) | 71.00 (63.00, 80.00) | 72.00 (63.00, 80.00) | 71.00 (62.42, 80.00) | Z = -0.839 | 0.401 | −0.133 | 70.00 (62.50, 79.38) | 71.00 (63.00, 79.00) | 70.00 (62.20, 80.00) | Z = -0.657 | 0.511 | −0.125 | |
| BMI, M (Q1, Q3) | 25.00 (22.86, 27.48) | 24.77 (23.01, 27.60) | 25.14 (22.58, 27.41) | Z = -0.050 | 0.960 | 0.029 | 24.77 (22.84, 27.22) | 24.60 (22.96, 27.30) | 24.82 (22.50, 27.12) | Z = -0.083 | 0.934 | −0.010 | |
| Course of AF, M (Q1,Q3) | 12.00 (2.00, 36.00) | 18.00 (4.00, 36.00) | 12.00 (1.50, 36.00) | Z = -2.424 | 0.015 | −0.091 | 12.00 (2.00, 36.00) | 18.00 (3.00, 36.00) | 12.00 (1.00, 33.00) | Z = -1.923 | 0.055 | −0.191 | |
| LAD, M (Q1, Q3) | 4.90 (4.30, 5.40) | 5.00 (4.40, 5.80) | 4.70 (4.30, 5.20) | Z = -2.625 | 0.009 | −0.405 | 4.90 (4.30, 5.40) | 4.90 (4.30, 5.70) | 4.80 (4.30, 5.30) | Z = -0.963 | 0.336 | −0.175 | |
| LVEF, M (Q1, Q3) | 56.00 (47.50, 61.00) | 56.00 (47.00, 62.00) | 57.00 (48.00, 61.00) | Z = -0.248 | 0.804 | −0.031 | 56.50 (47.50, 61.00) | 56.00 (49.00, 63.00) | 57.00 (47.00, 60.00) | Z = -1.436 | 0.151 | −0.264 | |
| Pre Qt, M (Q1, Q3) | 364.00 (328.00, 398.00) | 354.00 (310.00, 388.00) | 368.00 (335.00, 402.00) | Z = -2.090 | 0.037 | 0.241 | 359.00 (321.50, 392.50) | 364.00 (312.00, 395.00) | 356.00 (322.00, 393.00) | Z = -0.096 | 0.923 | −0.039 | |
| Pre Qtc, M (Q1, Q3) | 427.00 (396.75, 452.00) | 418.00 (393.00, 450.00) | 433.00 (404.50, 453.00) | Z = -1.247 | 0.212 | 0.151 | 424.50 (399.00, 453.25) | 421.00 (399.00, 452.50) | 429.00 (396.00, 455.00) | Z = -0.188 | 0.851 | −0.044 | |
| Pre Qrs, M (Q1, Q3) | 92.00 (86.00, 100.00) | 94.00 (88.00, 104.00) | 92.00 (86.00, 100.00) | Z = -1.615 | 0.106 | −0.293 | 94.00 (86.00, 102.00) | 94.00 (88.00, 102.00) | 92.00 (86.00, 102.00) | Z = -0.812 | 0.417 | −0.168 | |
| Gender, n (%) | χ2 = 5.282 | 0.022 | χ2 = 0.639 | 0.424 | |||||||||
| 0 | 81 (27) | 24 (19.83) | 57 (31.84) | 0.258 | 53 (26.24) | 24 (23.76) | 29 (28.71) | 0.109 | |||||
| 1 | 219 (73) | 97 (80.17) | 122 (68.16) | −0.258 | 149 (73.76) | 77 (76.24) | 72 (71.29) | −0.109 | |||||
| Smoking, n (%) | χ2 = 0.837 | 0.360 | χ2 = 1.253 | 0.263 | |||||||||
| 0 | 217 (72.33) | 91 (75.21) | 126 (70.39) | −0.105 | 149 (73.76) | 78 (77.23) | 71 (70.30) | −0.152 | |||||
| 1 | 83 (27.67) | 30 (24.79) | 53 (29.61) | 0.105 | 53 (26.24) | 23 (22.77) | 30 (29.70) | 0.152 | |||||
| Hypertension, n (%) | χ2 = 5.706 | 0.017 | χ2 = 0.178 | 0.673 | |||||||||
| 0 | 141 (47) | 67 (55.37) | 74 (41.34) | −0.285 | 105 (51.98) | 51 (50.50) | 54 (53.47) | 0.060 | |||||
| 1 | 159 (53) | 54 (44.63) | 105 (58.66) | 0.285 | 97 (48.02) | 50 (49.50) | 47 (46.53) | −0.060 | |||||
| Diabetes, n (%) | χ2 = 0.696 | 0.404 | χ2 = 0.040 | 0.841 | |||||||||
| 0 | 254 (84.67) | 105 (86.78) | 149 (83.24) | −0.095 | 173 (85.64) | 87 (86.14) | 86 (85.15) | −0.028 | |||||
| 1 | 46 (15.33) | 16 (13.22) | 30 (16.76) | 0.095 | 29 (14.36) | 14 (13.86) | 15 (14.85) | 0.028 | |||||
| Cerebral Infarction, n (%) | χ2 = 0.105 | 0.746 | χ2 = 1.702 | 0.192 | |||||||||
| 0 | 265 (88.33) | 106 (87.60) | 159 (88.83) | 0.039 | 178 (88.12) | 86 (85.15) | 92 (91.09) | 0.209 | |||||
| 1 | 35 (11.67) | 15 (12.40) | 20 (11.17) | −0.039 | 24 (11.88) | 15 (14.85) | 9 (8.91) | −0.209 | |||||
| Coronary Heart Disease, n (%) | χ2 = 6.651 | 0.010 | χ2 = 0.046 | 0.831 | |||||||||
| 0 | 250 (83.33) | 109 (90.08) | 141 (78.77) | −0.277 | 177 (87.62) | 89 (88.12) | 88 (87.13) | −0.030 | |||||
| 1 | 50 (16.67) | 12 (9.92) | 38 (21.23) | 0.277 | 25 (12.38) | 12 (11.88) | 13 (12.87) | 0.030 | |||||
A: amiodarone group; BMI: body mass index; LVEF: left ventricular ejection fraction; LAD: left atrial end-diastolic diameter; N: nifekalant group.
3.2. Efficacy
3.2.1. Immediate efficacy
There were 57 cases in the N group and 19 cases in the A group that were successfully converted immediately after medication, with success rates of 56.44 % (57/101) and 18.81 % (19/101), respectively (P < 0.001). Among them, 12 cases (11.88 %) in the N group and 4 cases (3.96 %) in the A group were directly converted to sinus rhythm (P < 0.05); 45 cases (44.56 %) and 15 cases (14.85 %) in each group were converted to atrial tachycardia (P < 0.001) (Table 2).
Table 2.
Immediate success rates.
| Variables | Total(n = 202) | N (n = 101) | A (n = 101) | Statistic | P |
|---|---|---|---|---|---|
| Final, n (%) | χ2 = 30.46 | 0<.001 | |||
| 0 | 126(62.38) | 44(43.56) | 82(81.19) | ||
| 1 | 76(37.62) | 57(56.44) | 19(18.81) | ||
| Final Info, n (%) | χ2 = 30.46 | 0<.001 | |||
| 0 * | 126(62.38) | 44(43.56) | 82(81.19) | ||
| 1 * | 16(7.92) | 12(11.88) | 4(3.96) | ||
| 2 * | 60 (29.70) | 45 (44.56) | 15(14.85) |
A: amiodarone group; Final: medical outcome (0 = AF, 1 = sinus rhythm / atrial tachycardia); Final. info: drug outcome details (0 = AF, 1 = sinus rhythm, 2 = atrial tachycardia); N: nifekalant group; χ2: Chi-square test; * Comparison between any two groups: P < 0.017.
3.2.2. Long-term efficacy
Follow-up of all patients at 3, 6, and 12 months showed that the long-term success rates in the N and A groups were 83.17 %vs 68.32 % (P < 0.05), 71.29 % vs 57.43 % (P < 0.05), and 63.37 %vs 49.50 % (P < 0.05), respectively. For patients who successfully converted immediately among the two groups, the long-term success rates at 3 and 12 months were 85.96 % vs 73.68 % (P > 0.05) and 75.44 % vs 52.63 % (P > 0.05), respectively, and at 6 months were 82.46 % vs 57.89 % (P < 0.05) (Table3).
Table 3.
Long-term success rate.
| Variables | Total (n = 202) | N (n = 101) | A (n = 101) | Statistic | P | Total (n = 76) | N (n = 57) | A (n = 19) | Statistic | P |
|---|---|---|---|---|---|---|---|---|---|---|
| 3mon, n(%) | χ2 = 6.06 | 0.014 | χ2 = 1.51 | 0.218 | ||||||
| 0 | 153 (75.74) | 84 (83.17) | 69 (68.32) | 63 (82.89) | 49 (85.96) |
14 (73.68) | ||||
| 1 | 49 (24.26) | 17 (16.83) | 32 (31.68) | 13 (17.11) | 8(14.04) | 5 (26.32) | ||||
| 6mon, n(%) | χ2 = 4.23 | 0.040 | χ2 = 4.75 | 0.029 | ||||||
| 0 | 130 (64.36) | 72 (71.29) | 58 (57.43) | 58 (76.32) | 47 (82.46) |
11 (57.89) | ||||
| 1 | 72 (35.64) | 29 (28.71) | 43 (42.57) | 18 (23.68) | 10 (17.54) |
8 (42.11) | ||||
| 12mon, n(%) | χ2 = 3.95 | 0.047 | χ2 = 3.51 | 0.061 | ||||||
| 0 | 114 (56.44) | 64 (63.37) | 50 (49.50) | 53 (69.74) | 43 (75.44) | 10 (52.63) | ||||
| 1 | 88 (43.56) | 37 (36.63) | 51 (50.50) | 23 (30.26) | 14 (24.56) | 9 (47.37) |
A: amiodarone group; N: nifekalant group; χ2: Chi-square test; 0 = sinus rhythm；1 = atrial tachycardia / AF.
3.2.3. Safety
The QT/QTc interval of patients in the two groups after medication was significantly prolonged compared to before medication (P < 0.001), yet did not significantly differ between groups (P > 0.05). In terms of procedure time, the N group required a longer time than the A group (P < 0.001). Only one case (0.99 %) in the N group experienced ventricular tachycardia, while no adverse effects occurred in the A group(P > 0.05) (Table 4).
Table 4.
Safety comparison.
| Variables | Total(n = 202) | N (n = 101) | A (n = 101) | Statistic | P |
|---|---|---|---|---|---|
| after.QT, M(Q1, Q3) | 391.00(363.50,432.00) | 388.00(360.00,436.50) | 398.00(365.00,432.00) | Z = -0.26 | 0.799 |
| after.QTc, M(Q1, Q3) | 459.50(427.50,485.00) | 462.00(430.00,491.00) | 454.00(424.50,482.00) | Z = -1.08 | 0.282 |
| after.QRS, M(Q1, Q3) | 96.00(88.00,104.00) | 96.00(88.00,104.00) | 96.00(88.00,103.00) | Z = -0.26 | 0.796 |
| △ QT, M (Q1, Q3) | 34.00(3.50,84.00) | 48.00(1.00,83.00) | 32.00(6.00,88.00) | Z = -0.84 | 0.399 |
| △ QTc, M (Q1, Q3) | 32.50(−8.25,72.00) | 36.00(−4.00,78.5.00) | 23.00(−14.00,59.00) | Z = -1.10 | 0.270 |
| △ QRS, M(Q1, Q3) | 4.00(−1.00,8.00) | 4.00(−4.00,8.00) | 4.00(0.00,8.00) | Z = -1.02 | 0.309 |
| Operation time, M (Q1, Q3) | 170.00 (139.75, 195.00) | 180.00 (150.00, 230.00) | 154. 5 0(130.00, 175 0.00) | Z = -5.47 | 0<.001 |
| Sinus bradycardia, n (%) | |||||
| No | 202 | 101 (100.00) | 101 (100.00) | ||
| Yes | 0 | 0 | 0 | ||
| Long QT, n (%) | |||||
| No | 202 | 101 (100.00) | 101 (100.00) | ||
| Yes | 0 | 0 | 0 | ||
| Hypotension, n (%) | |||||
| No | 202 | 101 (100.00) | 101 (100.00) | ||
| Yes | 0 | 0 | 0 | ||
| VT, n (%) | χ2 = 1.01 | >0.05 | |||
| No | 203 | 100 (99.01 %) | 101 (100.00) | ||
| Yes | 1 | 1 (0.99 %) | 0 | ||
| VF, n (%) | |||||
| No | 202 | 101 (100.00) | 101 (100.00) | ||
| Yes | 0 | 0 | 0 |
After. xxx: index after medication; M: Median, Q1:1st Quartile, Q3:3rd Quartile; VT: ventricular tachycardia; VF: ventricular fibrillation; △ xxx: difference in index before and after medication (after medication − before medication). χ2: Chi − square test; Z: Mann-Whitney test.
3.2.4. Subgroup analysis
We conducted subgroup analysis on age strata, gender, body mass index, medical history, course of AF, left atrial end-diastolic diameter, left ventricular ejection fraction, and QT/QTc interval to specifically understand whether nifekalant has better therapeutic effects on a certain population. The results showed that, especially for elderly patients with PeAF, a longer disease course, significant left atrial enlargement, left ventricular ejection fraction decrease and concomitant hypertension, nifekalant is more effective than amiodarone (P < 0.05) (Table5).
Table 5.
Subgroup analysis.
| Variables | n (%) | N | A | OR (95 %CI) | P |
|---|---|---|---|---|---|
| All patients | 202 (100.00) | 57/101 | 19/101 | 0.17 (0.09 ∼ 0.33) | 0<.001 |
| Gender | |||||
| Female | 53 (26.24) | 14/24 | 5/29 | 0.15 (0.04 ∼ 0.52) | 0.003 |
| Male | 149 (73.76) | 43/77 | 14/72 | 0.19 (0.09 ∼ 0.39) | 0<.001 |
| Smoking | |||||
| No | 149 (73.76) | 43/78 | 14/71 | 0.19 (0.09 ∼ 0.41) | 0<.001 |
| Yes | 53 (26.24) | 14/23 | 5/30 | 0.13 (0.04 ∼ 0.46) | 0.002 |
| Hypertension | |||||
| No | 105 (51.98) | 32/51 | 7/54 | 0.08 (0.03 ∼ 0.22) | 0<.001 |
| Yes | 97 (48.02) | 25/50 | 12/47 | 0.34 (0.15 ∼ 0.81) | 0.015 |
| Diabetes | |||||
| No | 173 (85.64) | 54/87 | 16/86 | 0.14 (0.07 ∼ 0.27) | 0<.001 |
| Yes | 29 (14.36) | 3/14 | 3/15 | 0.92 (0.15 ∼ 5.53) | 0.924 |
| Cerebral Infarction | |||||
| No | 178 (88.12) | 48/86 | 15/92 | 0.15 (0.07 ∼ 0.30) | 0<.001 |
| Yes | 24 (11.88) | 9/15 | 4/9 | 0.53 (0.10 ∼ 2.84) | 0.461 |
| Coronary Heart Disease | |||||
| No | 177 (87.62) | 55/89 | 17/88 | 0.14 (0.07 ∼ 0.28) | 0<.001 |
| Yes | 25 (12.38) | 2/12 | 2/13 | 0.91 (0.11 ∼ 7.72) | 0.930 |
| Age Sub | |||||
| <60 | 83 (41.09) | 25/41 | 6/42 | 0.10 (0.03 ∼ 0.29) | 0<.001 |
| ≥60 | 119 (58.91) | 32/60 | 13/59 | 0.25 (0.11 ∼ 0.55) | 0<.001 |
| BMI sub | |||||
| <24 | 80 (39.60) | 29/43 | 8/37 | 0.13 (0.05 ∼ 0.37) | 0<.001 |
| ≥24 | 122 (60.40) | 28/58 | 11/64 | 0.21 (0.09 ∼ 0.49) | 0<.001 |
| Course of AF sub | |||||
| <12 | 93 (46.04) | 27/44 | 8/49 | 0.12 (0.04 ∼ 0.31) | 0<.001 |
| ≥12 | 109 (53.96) | 30/57 | 11/52 | 0.24 (0.10 ∼ 0.56) | 0<.001 |
| LAD Sub | |||||
| <45 | 20 (9.90) | 9/11 | 2/9 | 0.06 (0.01 ∼ 0.57) | 0.014 |
| ≥45 | 182 (90.10) | 48/90 | 17/92 | 0.19 (0.10 ∼ 0.38) | 0<.001 |
| LVEF Sub | |||||
| <50 | 61 (30.20) | 15/26 | 7/35 | 0.18 (0.06 ∼ 0.57) | 0.003 |
| ≥50 | 141 (69.80) | 42/75 | 12/66 | 0.17 (0.08 ∼ 0.37) | 0<.001 |
| Pre Qt Sub | |||||
| <450 | 196 (97.03) | 57/99 | 17/97 | 0.15 (0.08 ∼ 0.30) | 0<.001 |
| ≥450 | 6 (2.97) | 0/2 | 2/4 | NA | 0.998 |
| Pre Qtc Sub | |||||
| <450 | 143 (70.79) | 39/74 | 14/69 | 0.22 (0.11 ∼ 0.47) | 0<.001 |
| ≥450 | 59 (29.21) | 18/27 | 5/32 | 0.09 (0.03 ∼ 0.32) | 0<.001 |
A: amiodarone group; BMI: body mass index; CI: Confidence Interval; LAD: left atrial end-diastolic diameter; LVEF: left ventricular ejection fraction; OR: Odds Ratio, N: nifekalant group.
3.2.5. Logistic regression analysis
The intraoperative medication and baseline features were included as independent variables, and the recurrence at 12-month was the dependent variable. The univariate and multivariate logistic regression analysis showed that intraoperative medication [P < 0.05, 2.08 (1.15 ∼ 3.76)], left atrial end-diastolic diameter [P < 0.05, 1.60 (1.13 ∼ 2.28)]and course of AF [P < 0.05, 1.01 (1.01 ∼ 1.02)] were independent risk factors for the 12-month recurrence of PeAF (Table 6).
Table 6.
Logistic regression analysis.
| Variables | Univariate |
Multivariate |
|||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| β | S.E | Z | P | OR (95 %CI) | β | S.E | Z | P | OR (95 %CI) | ||
| Group | |||||||||||
| N | 1.00 (Reference) | 1.00 (Reference) | |||||||||
| A | 0.57 | 0.29 | 1.98 | 0.048 | 1.76 (1.01 ∼ 3.10) | 0.73 | 0.30 | 2.43 | 0.015 | 2.08 (1.15 ∼ 3.76) | |
| Gender | |||||||||||
| female | 1.00 (Reference) | ||||||||||
| male | −0.09 | 0.32 | −0.29 | 0.769 | 0.91 (0.48 ∼ 1.71) | ||||||
| Smoking | |||||||||||
| no | 1.00 (Reference) | ||||||||||
| yes | −0.11 | 0.32 | −0.35 | 0.725 | 0.89 (0.47 ∼ 1.68) | ||||||
| Hypertension | |||||||||||
| no | 1.00 (Reference) | ||||||||||
| yes | −0.10 | 0.28 | −0.36 | 0.721 | 0.90 (0.52 ∼ 1.58) | ||||||
| Diabetes | |||||||||||
| no | 1.00 (Reference) | ||||||||||
| yes | 0.55 | 0.40 | 1.35 | 0.176 | 1.73 (0.78 ∼ 3.81) | ||||||
| Cerebral Infarction | |||||||||||
| no | 1.00 (Reference) | ||||||||||
| yes | 0.48 | 0.44 | 1.11 | 0.268 | 1.62 (0.69 ∼ 3.82) | ||||||
| Coronary Heart Disease | |||||||||||
| no | 1.00 (Reference) | ||||||||||
| yes | −0.17 | 0.44 | −0.38 | 0.701 | 0.85 (0.36 ∼ 1.99) | ||||||
| Age | 0.02 | 0.02 | 1.09 | 0.274 | 1.02 (0.99 ∼ 1.05) | ||||||
| BMI | −0.01 | 0.04 | −0.19 | 0.849 | 0.99 (0.91 ∼ 1.08) | ||||||
| Course of AF | 0.01 | 0.01 | 2.17 | 0.030 | 1.01 (1.01 ∼ 1.02) | 0.01 | 0.01 | 2.10 | 0.036 | 1.01 (1.01 ∼ 1.02) | |
| LAD | 0.46 | 0.17 | 2.66 | 0.008 | 1.58 (1.13 ∼ 2.22) | 0.47 | 0.18 | 2.64 | 0.008 | 1.60 (1.13 ∼ 2.28) | |
| LVEF | −0.01 | 0.01 | −1.01 | 0.314 | 0.99 (0.96 ∼ 1.01) | ||||||
| Pre Qt | 0.00 | 0.00 | 0.42 | 0.673 | 1.00 (1.00 ∼ 1.01) | ||||||
| Pre Qtc | −0.00 | 0.00 | −0.00 | 0.997 | 1.00 (0.99 ∼ 1.01) | ||||||
| Pre Qrs | 0.01 | 0.01 | 0.77 | 0.439 | 1.01 (0.99 ∼ 1.02) | ||||||
A: amiodarone group; OR: Odds Ratio, CI: Confidence Interval; BMI: body mass index; LAD: left atrial end-diastolic diameter; LVEF: left ventricular ejection fraction; N: nifekalant group;
4. Discussion
Nifekalant, as a novel antiarrhythmic drug class III, is highly selective for blocking the potassium currents and has no effects on the sodium currents, calcium currents and β-adrenergic receptors[8], [14]. It exerts a potent anti-arrhythmic action and has the potential to be used in refractory atrial fibrillation. Our exploratory study demonstrated that use of nifekalant could effectively improve procedure outcomes in patients with PeAF during RFCA.
Currently, despite the procedure outcome of PeAF has been improved, it is still unsatisfactory. When RFCA fails to terminate PeAF, some centers often resort to electrical cardioversion or antiarrhythmics. While electrical cardioversion is effective and expeditious, it necessitates sedation or anesthesia. And even with antiarrhythmic drug treatment after electrical cardioversion, nearly half of patients will experience AF recurrences, which may be attributed to the duration of AF, left atrial size, and low-energy shocks. Moreover, it can cause some adverse events including myocardial injury and model displacement caused by muscle contraction and is closely related to energy levels[15], [16], [17], [18]. Cardioversion led by drugs might avoid the above disadvantages.
Although amiodarone, one of the class III agents, is widely used for various arrhythmias and shows notable efficacy in AF management, it has additional effects on other ion channels and the sympathetic activity[19]. Consequently, it exhibits negative inotropic and decreasing blood pressure, which could be not conducive to AF patients with severe heart failure. Nifekalant is a pure potassium channel blocker, without inducing negative inotropic effects and reducing cardiac function and affecting hemodynamic status[8], [14], [20]. Recent research has shown that nifekalant can lower the defibrillation threshold for AF [9]. Therefore, nifekalant may be more advantageous in cardioversion of AF. Hu et al.[21]suggested that nifekalant significantly prolongs the effective refractory period by blocking antegrade action potential conduction, making it effective in patients with pre-excited AF. To our knowledge, there are currently no relevant studies comparing the efficacy of nifekalant and amiodarone in patients with PeAF who were unsuccessful converted undergone ablation. Our research found that nifekalant was more effective than amiodarone in enhancing the immediate success rates in patients with PeAF, which may be supported by the prolongation of action potential duration and effective refractory period of cardiomyocytes[20], [22], [23].
The present study also found that the one-year success rates of the nifekalant group were significantly higher than that of the amiodarone group. The atrial tachycardia usually due to the related atrial circuit abnormalities, which are significant factors in recurrence of AF after pulmonary vein isolation [24]. Hence, any antiarrhythmic is unlikely to permanently suppress recurrence of atrial arrhythmias, and the preferred treatment strategy should aim to permanently isolate all abnormal circuits during re-ablation procedure[25]. Research has shown that ablation strategy focused on ectopic lesion formation are linked to lower recurrence rates of AF following pulmonary vein isolation[26]. Nevertheless, A large randomized controlled trial conducted by Vogler et al. indicated that for patients with PeAF, a stepwise approach including pulmonary vein isolation, ablation of complex fractionated electrograms, and additional linear ablation lines did not yield superior results compared to pulmonary vein isolation alone[27]. Consequently, in our study, following a similar conventional ablation, we further utilized antiarrhythmics to identify atrial tachycardia and performed targeted ablation to eliminate abnormal circuits, which might lead to improved outcomes in patients with persistent atrial fibrillation undergone ablation procedure. Compared to amiodarone, we demonstrated that nifekalant revealed more potential trigger points for atrial tachycardia, which helped to achieve thorough ablation by mapping and targeted ablation of those arrhythmias trigger points and associated maintenance circuits. Kumagai et al[28] reported that nifekalant is helpful to localize areas of complex fractionated atrial electrograms during ablation procedure, which was consistent with our results. Moreover, contributing to evaluate whether the ablation is complete and effective by using nifekalant during the procedure, while also prevented excessive ablation. Our results can also facilitate the development of personalized ablation strategies to provide precision therapy.
As for safety, only one case in the nifekalant group occurred ventricular tachycardia, there was no obvious difference in the overall incidence of adverse events between two groups, aligning with the previous studies[9], [21]. While nifekalant and amiodarone prolong the QT interval, nifekalant has a shorter half-life[7], [19]. Thus, a single intravenous injection of nifekalant seems to be safe. Additionally, our results indicated that nifekalant proved to be superior efficacy to amiodarone, especially for patients with elderly, longer course of AF, significant left atrial enlargement and left ventricular ejection fraction decrease. And it was also confirmed prior studies[10], [21]. The regression analysis identified the type of intraoperative medication and course of AF as independent risk factors for the 12-month recurrence of the patients with PeAF.
This study has several limitations. Firstly, it is a retrospective cohort study, all inherent limitations of retrospective studies apply to it as well. Secondly, the study predominantly comprises participants from a single center, with a small sample size. Thirdly, Follow-up time is relatively short and the ECG documentation during the follow-up did not utilize continuous recording types. Therefore, a larger sample size with multiple centers prospective randomized controlled study is needed to confirm the results.
5. Conclusion
Intravenous administration of antiarrhythmics during the procedure is a potential option for treatment of patients with PeAF who persists through RFCA. Compared to amiodarone, the commonly used drugs, nifekalant has the ability to reveal a higher occurrence of atrial tachycardia, for guiding the targeted and personalized ablation, thereby enhancing the immediate success rates of AF in a more efficient manner, as well as the long-term success rates.
6. Funding Sources
This work was financially supported by the International Science and Technology Cooperation Project of Hubei Province (No.2023EHA046) and National Key R&D Program of China (No. 2022YFE0209900).
CRediT authorship contribution statement
Tingqiong Ma: Writing – original draft, Data curation. Chunxia Zhao: Supervision. Luyun Wang: Supervision. Yang Bai: Supervision. Lei Lei: Supervision. Li Ni: Supervision. Mei Hu: Supervision. Guangzhi Chen: Writing – review & editing, Supervision, Funding acquisition. Yan Wang: Writing – review & editing, Supervision, Resources, Funding acquisition.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Contributor Information
Guangzhi Chen, Email: chengz2003@163.com.
Yan Wang, Email: newswangyan@tjh.tjmu.edu.cn.
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