Table 1.

Clinical studies testing ranolazine for AF treatment.

Study	Population Studied (N, Age, %Male)	Study Design	AF Detection Method, Surveillance Duration	Results
Murdock 2008 [126] #	Recurrent AF with failure to AF ablation or anti-arrhythmic behavior 7, 67 ± 9, 57%	Oral RN (500–1000 mg/BID) after stopping all other anti-arrhythmic therapy	Not reported	AF conversion: 5/7 AF recurrence: 4/7 remained in NSR 1 AF event at 3 months and 6 months
Miles 2011 [127] a	Post CABG AF 182, 66.7 ± 9.3, 70% (intervention arm) 211 64.9 ± 10.9, 77% (control arm)	Intervention arm: 1500 mg RN before surgery, 1000 mg RN BID post-op for 10–14 days Control arm: 400 mg amiodarone before surgery, 200 mg amiodarone BID post-op 10–14 days	Continuous ECG monitoring throughout hospitalization	Incidence of POAF: AF 26.5% in control group vs. 17.5% in RN-treated group (p = 0.035)
Fragakis 2012 [117] c	New onset AF (<48 h from diagnosis) 25, 62 ± 8, 60% (intervention arm) 26, 64 ± 7, 69% (control arm)	Intervention arm:1500 mg RN daily and IV amiodarone Control arm: IV amiodarone (loading dose: 5 mg/kg in 1 h followed by 50 mg/h for 24 h or until cardioversion)	Continuous ECG in CCU for 24 h followed by >1 day inpatient	Conversion rate to NSR: 65% in control vs. 88% in RN-treated group (p = 0.056) Time to conversion: control 14.6 ± 5.3 h vs. RN-treated 9.8 ± 4.1 h (p < 0.001)
Murdock 2012 [128] #	Recurrent AF with electro-cardioversion failure 25, 62 ± 11, 76%	2000 mg RN given after failed electrocardioversion attempt, repeat electrocardioversion after 3–4 h of administration	Not reported	AF conversion: 17/25 3 patients spontaneously converted before the second attempt at EC within 4 h of ranolazine
Tagarakis 2013 [129] c	Post-CABG AF 34, NA, NA (intervention arm) 68, NA, NA (control arm)	Intervention arm: 375 mg RN BID 3 days prior to operation until discharge Control arm: usual care	Continuous ECG monitoring for first 24 h followed by ECG monitoring every 4 h until discharge	Incidence of POAF: control 30.8% vs. RN-treated 8.8% (p < 0.001)
Koskinas 2014 [118] c	New onset AF (<48 h from diagnosis) 61, 66 ± 11, 41% (intervention arm) 60, 64 ± 9, 48% (control arm)	Intervention arm: 1500 mg RN daily and IV amiodarone Control: IV amiodarone (loading dose: 5 mg/kg in 1 h followed by 50 mg/h)	Continuous ECG monitoring in the CCU for 24 h	Conversion rate at 12 h: control 32% vs. RN-treated 52% (p = 0.021) Conversion rate at 24 h: control 70% vs. RN-treated 87% (p = 0.024) Time to conversion: control 13.3 ± 4.1 h vs. RN-treated 10.2 ± 3.3 h (p < 0.001) Modest QT prolongation in both the groups, no serious adverse reactions, and no pro-arrhythmic events.
Simopuolos 2014 [119] c	Post-CABG AF 20, 69 ± 7, 70% (intervention arm) 21, 67 ± 8, 60% (control arm)	Intervention arm: 500 mg RN (loading dose) followed by 375 mg RN BID and IV amiodarone Control arm: IV amiodarone: 300 mg in 30 min followed by 750 mg in 24 h, then 200 mg BID for one week and then 200 mg daily for 1 week	Continuous ECG monitoring for first 24 h followed by ECG every 4 h, monitoring until discharge	Time to conversion to NSR: control 37.2 ± 3.9 h vs. RN-treated 19.6 ± 3.2 h (p < 0.001)
Scirica 2015 (MERLIN) [130] c	Patients hospitalized for NSTEMI 3162, 17% >75 yrs, 66.8% (intervention arm) 3189, 18% >75 yrs, 63.7% (control arm)	Intervention arm: IV 200 mg RN with 80 mg/h infusion for 12–96 h, then 1000 mg oral RN BID Control arm: placebo plus standard medical intervention	Continuous ECG monitoring for 7 days Median clinical follow-up at 12 months	AF burden—episodes detected on continuous ECG in first 7 days: control 55 (1.7%) vs. RN-treated 75 (2.4%) (p = 0.08) New onset AF: Clinically insignificant: control 7 vs. RN-treated 5 Paroxysmal: control 48 vs. RN-treated 18 Chronic: control 20 vs. RN-treated 28 (p < 0.01) One-year AF events: control 4.1% vs. RN-treated 2.9% (p = 0.01)
De Ferrari 2015 (RAFFAELLO) [131] c	Persistent AF, 2 h after successful cardioversion 65, 66.9 ± 11.8, 70.8% (375 mg RN) 60, 65.5 ± 8.5, 85% (500 mg RN) 58, 63.6 ± 11.3,79.3 (750 mg RN) 55, 65.2 ± 9.5, 74.5% (control arm)	Intervention arm: either oral 375 mg BID, 500 mg BID, or 750 mg BID ranolazine Control arm: placebo	Transtelephonic electrocardiogram for 16 weeks and 12 lead ECG at 1 week, 2 months, and 4 months	AF recurrence: control 56.4% vs. 375 mg (56.9%) vs. 500 mg (41.7%) vs. 750 mg (39.7%) AF in higher dose vs. control (p = 0.053)
Tsanaxidis 2015 [120] *,c	New onset AF 36, 67 ± 10,25% (intervention arm) 29, 62 ± 11,55% (control arm)	Intervention arm: 1000 mg RN once + IV amiodarone Control arm: IV amiodarone (loading dose: 5 mg/kg in 1 h followed by 50 mg/h)	Not reported	Time to conversion to NSR: control 24.4 ± 4.1 vs. 8.1 ± 2.2
Bekeith 2015 [132] *,b	POAF 27, NA, NA (intervention arm) 27, NA, NA (control arm)	Intervention arm: 1000 mg RN BID for 48 h prior to surgery and 2 weeks post-op Control: placebo	ECG monitoring in patient followed by holter monitor 2 weeks post-discharge	Incidence of AF: control 8 (30%) vs. RN-treated 5 (19%) (p = 0.530)
Hammond 2015 [133] a	POAF 69, 59.7 ± 10.8, 68.1% (intervention arm) 136, 62.2 ± 11.8, 56.6% (control arm)	Intervention arm: 1000 mg RN BID starting on day of surgery for 7 days or until discharge Control arm: standard therapy	Not reported	POAF occurrence: 41.9% vs. 10.1% (p < 0.0001)
Reiffel 2015 (HARMONY) [121] a	Paroxysmal AF with recent dual-chamber pacemaker placement 26, 70 ± 10.8, 39% (intervention arm) 52, 73.5 ± 11.5, 44.5% (control arm)	Intervention arm: 750 mg RN BID, dronedarone, or both Control: placebo	Dual-chamber pacemaker, 4-week run-in period followed by a 12-week treatment period	AF burden: % difference vs. placebo dronedarone 9% (p = 0.78), RN −20% (p = 0.49), RN + 150 mg dronedarone −43% (p = 0.072), RN + 225 mg dronedarone (p = 0.008)
Tsanaxidis 2017 [122]	New onset AF (<48 h from onset) 92, 70 ± 10, 41% (intervention arm) 81, 67 ± 11, 50.6% (control arm)	Intervention arm: 1000 mg RN once and IV amiodarone Control arm: IV amiodarone (loading dose: 5 mg/kg in 1 h followed by 50 mg/h)	Not reported	Time to conversion: control 19.4 ± 4.4 vs. RN-treated 8.6 ± 2.8 (p < 0.0001) Conversion rate at 24 h: control 58% vs. RN-treated 98% (p < 0.001)
Simopoulos 2018 [123]	POAF in patients with HFrEF vs. HFpEF 511, 65 ± 9, 87% (HFrEF arm) 301, 66 ± 10, 85% (HFpEF arm)	Intervention arm: 500 mg RN followed by 375 mg RN after 6 h and 375 mg RN BID thereafter and amiodarone Control arm: IV amiodarone (300 mg in first 30 min + 1125 mg over next 36 h)	Not reported	Time to conversion: HFrEF: control 24.3 ± 4.6 vs. RN-treated 10.4 ± 4.5 HFpEF: control 26.8 ± 2.8 vs. RN-treated 12.2 ± 1.1
Meta-Analysis
Guerra 2017 [134]				AF event (new onset or recurrence): OR 0.47; 95% CI 0.29–0.76 (p = 0.003) POAF: OR 0.29; 95% CI 0.11–0.77 (p = 0.03) Non-operative AF: OR 0.70; 95% CI 0.54–0.83 (p = 0.005) Successful cardioversion vs. amiodarone alone: OR 3.11; 95% CI 1.42–6.79 (p = 0.004) Time to cardioversion: SMD −2.83 h; 95% CI from −4.69 to −0.97 h (p < 0.001)
Gong 2017 [135]				AF event: RR 0.67, 95% CI 0.62–0.87 (p = 0.002) Successful cardioversion vs. amiodarone alone: RR 1.23, 95% CI 1.08–1.40 (p = 0.002) Time to cardioversion: WMD –10.38 h; 95% CI from −18.18 to −2.57 h (p < 0.009)

AF = atrial fibrillation, BID = twice daily, CABG = coronary artery bypass surgery, HFpEF = heart failure with preserved ejection fraction, HFrEF = heart failure with reduced ejection fraction, NSR = normal sinus rhythm, NSTEMI = non-ST elevation myocardial infarction, POAF = post-operative AF, RN = ranolazine. ^# Case series. * Abstract. ^a Included in Guerra et al. meta-analysis. ^b Included in Gong et al. meta-analysis. ^c Included in both Guerra et al. and Gong et al. meta-analyses.