Table 16.

Main potential AAD combinations

Potential AAD combinations424  (Supported by some evidencea)
Class #1	AAD #1	Class #2	AAD #2	Rationale	Objective	Study, reference
0	Ivabradine	II	β-blockers	Summative complementary effects	Inappropriate sinus tachycardia	425
Ia	Quinidine	Ia	Disopyramide	Combined reduced doses to minimize side effects	Decrease gastrointestinal intolerance (constipation for disopyramide, diarrhoea for quinidine)b	426,427
		Ib	Mexiletine	Complementary actions on the refractory period (Ia prolongs; Ib shortens) Quinidine favours mexiletine biding to the inactivated state of the Na+ channel	VAs	428–430
		IV	Verapamil	Verapamil may prevent: AAD Class I induce EADs Fast AV conduction during AF due to the vagolytic effect of quinidine	AAsb and VAs	431 , PAFAC432, SOPAT433
Ic	Flecainide	Ib	Mexiletine	Summative effects	VAs	434
	Flecainide, propafenone	II, IV	β-blockers, CCBs	Complementary effects on myocardium and AV nodec	Rate control of AF/AFL/ type Ic AFL and SVT prevention/terminationc	92
III	Amiodarone	Ia/Ib	Quinidine/Mexiletine	Complementary effects on ventricular conduction and refractoriness	VAs	435–437
		Ic/Id	Flecainide/propafenone/ranolazine	Complementary effects on conduction and refractoriness	AAs and VAS	438–440
		II	β-blockers	Complementary effects on myocardium and adrenergic tone	SHD VAs	OPTIC91
	Dronedarone	Id	Ranolazine	Combined reduced doses to potentiate efficacy and minimize side effects (constipation for ranolazine, diarrhoea for dronedarone)	AF	HARMONY76
	Sotalol	Ib/Ic	Mexiletine/flecainided	Complementary effects on conduction and refractoriness	VAs in ARVC	441,442,
IIa	β-blockers	0, I, IIb, IId, III		Blocks sympathetic stimulation enhancing the efficacy and/or safety of other AADs	AAs and VAs	443
IV	CCBs	IId	Digoxine	Summative effects	Rate control of AF	444

Uncertain AAD combinations (limited data on efficacy and safety)
Class #1	AAD #1	Class #2	AAD #2	Rationale	Objective
III	Dronedarone	IV	Verapamil, diltiazemf	Additional rate control to that of dronedarone	AAs	Limited data
III	Sotalol dofetilide	Id	Ranolazine	Ranolazine may mitigate EADs caused by Class III drugs, reducing TdP risk	AAs and VAs	Limited data445,446

Potentially hazardous AAD combinations (To avoid or to be used at reduced doses)
Class #1	AAD #1	Class #2	AAD #2	Rationale	Risk
Ia	Disopyramide	IV	CCBsg	Both reduce cardiac contractility	Heart failure and shock	447
Id	Ranolazine	Ia	Quinidine	Both are metabolized primarily by CYP3A4	TdP
			Disopyramide	Both may produce constipation	Constipation
		Ib Ic	Mexiletine Flecainide	Both have CNS effects	Tremor
II	β-blockers	IV	CCBs	Both depress the SN, AV conduction and cardiac contractility	AV block
III	Sotalol	II IV	β-Blockers CCB	Both depress the SN, AV conduction, and cardiac contractility	Bradycardia
	Sotalol/dofetilide	Ia	Quinidine	Both prolong the QT interval	TdP	448,449
	Dronedarone	Id	Digoxin	Dronedarone decreases renal clearance of digoxin	Digitalis toxicity	105
	Dofetilide	IV	CCBs	CCBs increase dofetilide levels	TdP

Column #1 lists AADs commonly used as the first-choice drug, while Column #2 includes AADs typically added as complementary therapy when the primary drug fails to control the arrhythmia or may result in pro-arrhythmia or other adverse effects. This order may be reversed depending on specific circumstances.

Abbreviations: AA, atrial arrhythmias; ARVC, arrhythmogenic right ventricular dysplasia; AF, atrial fibrillation; AFL, atrial flutter; AV, atrioventricular; CCB, calcium channel blockers; EADs, early after depolarizations; SN, sinus node; SHD, structural heart disease; SVT, supraventricular tachycardia; VA, ventricular arrhythmias; TdP, torsades de pointes; VA, ventricular arrhythmias; VF, ventricular fibrillation; VM, Vaughan Williams; VT, ventricular tachycardia.

^aCombining AADs increases risks and necessitates careful evaluation of alternatives and patient conditions, along with close dose adjustments and ECG monitoring to mitigate myocardial depression and pro-arrhythmia. Most evidence comes from small, non-controlled studies.

^bIn general, ablation is advised before quinidine for AF treatment.

^cContraindicated in patients with structural heart disease due to the risk of myocardial contraction depression and heart failure.

^dFlecainide may potentiate the myocardial contraction depression effect of sotalol.

^eConsider reducing the dose of digoxin and monitoring serum levels closely due to the risk of toxicity. CCB can increase digoxin levels by 50–75% through inhibition of P-glycoprotein activity, which decreases renal tubular elimination of digoxin.

^fDiltiazem, verapamil, and dronedarone are substrates and inhibitors of CYP3A4, and their concurrent use can increase plasma concentrations of each drug, potentially amplifying their pharmacological effects and side effects. When rate control is required, combining dronedarone with a β-blocker is generally preferred over CCBs. Additionally, both dronedarone and CCBs can depress AV conduction, increasing the risk of bradycardia or heart block. Therefore, the combination of dronedarone with CCBs must only be used with caution and under close clinical and ECG monitoring.

^gWith caution to improve symptoms in hypertrophic cardiomyopathy.