Pharmacologic Therapy for Adult Congenital Heart Disease

Pharmacologic Therapy for Adult Congenital Heart Disease

Dan G. Halpern

Rebecca Pinnelas

Frank Cecchin


As survival of congenital heart disease patients continues to improve, the role of pharmacologic therapy is pivotal in the care of adults with congenital heart disease (ACHD), complementing surgical, and interventional therapies. Wide-ranging pathology, underpowered trials, reliance on retrospective studies, and science extrapolated from acquired cardiovascular disease literature challenges the field. However, newly published evidence-based guidelines, together with growing research alliances and large international registries, help standardize care and improve outcomes.1,2,3

Initiation of chronic multidrug therapy at a young age raises long-term concerns. Polypharmacy, including noncardiac medications, is twice as prevalent among ACHD patients compared with the general population. Additionally, chronic multidrug therapy has been associated with a fourfold increased risk of mortality and adverse drug events, only in part explained by the congenital heart disease.4 Therefore, prescribing clinicians should judiciously weigh the strength of the evidence in favor of pharmacologic therapy against potential long-term drug side effects. This chapter provides an overview of medical therapies recommended and used for the most common congenital heart pathologies Table 105.3. Individuals with acquired heart disease or risk factors for such should be treated according to American College of Cardiology (ACC)/American Heart Association (AHA) guidelines.


Hemodynamic changes secondary to congenital heart disease may have profound effects on the pharmacokinetics of drugs, requiring dosing considerations and adjustments. Renal function may be attenuated by reduced cardiac output, renal venous congestion, and cyanosis. Hepatic congestion and fibrosis—as may occur in the setting of Fontan palliation for single ventricle or right-sided heart failure—may also affect the metabolism of drugs. Additionally, hepatitis C infection is a common finding in congenital patients treated with blood transfusions before 1992 and may lead to early cirrhosis. Protein-losing enteropathy in patients with Fontan circulation causes delayed drug absorption and hypoalbuminemia, which increases the free fraction of protein-bound medications.

Right-to-left shunting may affect physiologic first-pass metabolism and drug concentration. In an animal model of right-to-left shunting, administration of lidocaine bypassed the drug’s first-pass metabolism within the lung, which resulted in a doubling of its peak arterial concentration and neurotoxicity at two-thirds of the traditional dose.5 Conversely, prodrugs metabolized in the liver may actually have reduced drug concentrations with right-to-left shunting.

The basic tenets of medication administration in congenital heart patients include initiation of low dosages with careful and gradual increase of the dose based on hemodynamic response and side effects. Progressive dosing should be based on changing hemodynamics and routine hepatic and renal laboratory work. As some medications may increase the risk of arrhythmia, event monitors (with multiweek monitoring capabilities) are useful in identifying arrhythmia during and after medication titration.


Arrhythmia is the leading cause of hospital admissions in the ACHD population (see Table 105.1). The basis for this high-arrhythmic load is a combination of cardiac developmental abnormalities and lifelong accumulation of arrhythmic substrate. Congenital heart disease is often associated with conduction system anomalies like accessory pathways and maldevelopment of the sinus and atrioventricular nodes. Additionally, the structure of the cardiac anomaly—such as the conal septum in tetralogy of Fallot (TOF)—may contribute to the genesis of ventricular tachycardia. Accumulation of multiple sutures or surgical scar lines, cyanosis, pressure, and volume-overloaded myocardium also contribute to the arrhythmia substrate in those with ACHD.6 Not surprisingly, the burden of arrhythmia is directly proportional to the complexity of the cardiac lesion and the number of prior corrective cardiac surgeries. Suture lines, scarring, and fibrosis create anatomic barriers, which aid in propagation of the arrhythmic wavefront. While many of these arrhythmias can be successfully treated with a catheter or surgical ablation, long-term antiarrhythmic drug therapy is commonly used adjunctively since some mechanisms can be only modified and not completely cured. There is no role for drug treatment of chronic bradyarrhythmia, which can only be effectively treated with cardiac pacing.

Pharmacotherapy for Atrial Tachyarrhythmia

Pharmacotherapy recommendations for atrial tachyarrhythmia not only take into consideration the congenital heart lesion complexity but should also consider additional factors such as coexisting sinus node dysfunction, impaired atrioventricular (AV) nodal conduction, systemic or subpulmonary ventricular dysfunction, associated therapies, child-bearing potential, and acquired comorbidities.7 Simple and moderate complexity lesions such as atrial septal defect (ASD), ventricular septal defect (VSD), Ebstein anomaly, and TOF may be treated with Class IC antiarrhythmic agents (eg, flecainide and propafenone) if ventricular dysfunction is absent. Complex lesions with arrhythmias, such as single ventricles with Fontan palliation or cyanotic congenital heart disease, are treated with Class III antiarrhythmic agents (eg, amiodarone and sotalol). Specific considerations and dosing strategies vary among the different congenital lesions and antiarrhythmic drugs. Consultation with an electrophysiologist who has expertise with congenital heart disease is highly recommended.

Class IC antiarrhythmic drugs may have proarrhythmic effects in patients with structural heart disease and should not be used in the presence of hepatic dysfunction, prolonged PR interval (>250 ms), coronary artery disease, or moderately to severely depressed systolic dysfunction of a systemic or subpulmonary ventricle. In addition, Class IC antiarrhythmic agents can organize atrial fibrillation into a rapid atrial flutter (eg, with 1:1 conduction), thus requiring concomitant use of an AV nodal blocking agent.

Class III antiarrhythmic agents are associated with QTc prolongation, which could be challenging to assess in the setting of a significantly prolonged QRS complex in many ACHD patients. One strategy of correcting the QT interval in the setting of intraventricular conduction delay is to use the following equation: QTc (corrected) = (QT-(QRS-120))/RR0.5.8

Mixed data regarding the proarrhythmic potential of sotalol exist; therefore, it is considered a second-line therapy. General guidelines for atrial fibrillation support the use of sotalol (Class IIa indication) for maintenance of sinus rhythm in patients with little or no heart disease, baseline QT interval less than 460 ms, normal serum electrolytes, creatinine clearance greater than 40 mL/min, and absence of risk factors associated with Class III antiarrhythmic drug-related proarrhythmia. Holter monitoring and stress testing are recommended after achieving the sotalol loading dose to rule out proarrhythmia. A recent large retrospective analysis showed that sotalol was safe and effective in low dosages in the ACHD population, but it was associated with significant bradycardia in the Fontan population.9 Amiodarone has multiple toxicities (cardiac, lung, liver, thyroid, skin, eyes, and central nervous system) as well as multiple drug interactions. Amiodarone requires pulmonary toxicity monitoring (baseline chest x-ray and pulmonary function tests, then annual chest x-ray) together with frequent liver and thyroid function testing before initiation of therapy and then every 3 to 6 months thereafter. Dose reduction of digoxin and warfarin is required when administered concomitantly with amiodarone. When using antiarrhythmic drugs, it is always important to reassess the effects of sinus node function and AV node function. Bradycardia is a side effect of treatment with beta-blockers, calcium channel blockers, and Class III antiarrhythmic drugs. If their use is essential, permanent pacing may be needed to achieve effective antiarrhythmic drug dosages.

Arrhythmia-Specific Considerations

Intra-atrial reentrant tachycardia or “incisional tachycardia” is the most common tachyarrhythmia observed in ACHD
patients. It can be a component of typical atrial flutter (peritricuspid valve reentry) or unrelated. The circuit propagates around right-atrial atriotomy incisions, scars from chronic fibrosis, ASD patches, and other anatomic barriers. It is often resistant to primary antiarrhythmic drug therapy and may require rate-controlling agents and chronic anticoagulation. Radiofrequency ablation may be curative as a primary treatment.

Accessory pathways or Wolff-Parkinson-White (WPW) syndrome is highly prevalent in Ebstein anomaly and congenitally corrected transposition of the great arteries (L-TGA). Radiofrequency catheter ablation of the accessory pathway is mainstay treatment. Treatment of supraventricular tachycardia (SVT) episodes in patients with WPW depends on the directionality of the circuit. Orthodromic AV reciprocating tachycardia (AVRT), appearing as a narrow complex tachycardia in which antegrade conduction occurs through the AV node with retrograde conduction through the accessory pathway. It is treated with vagal maneuvers or AV nodal blocking agents (ie, adenosine, beta-blockers, and calcium blockers) for acute termination, and beta-blockers for chronic treatment. Antidromic AVRT, in which antegrade conduction occurs through the accessory pathway with retrograde conduction through the AV node, appears as a wide complex tachycardia and is treated acutely with intravenous procainamide infusion. Atrial flutter or fibrillation in the setting of WPW syndrome should be treated with cardioversion, intravenous procainamide, or intravenous ibutilide. AV nodal blocking agents are contraindicated in antidromic AVRT and WPW syndrome with atrial fibrillation, as they may increase conduction through the accessory pathway. Thus, when unsure of the arrhythmic diagnosis, it may be safer to initially use procainamide.

Atrial fibrillation increases in prevalence with age and is observed in left-sided cardiac lesions such as congenital mitral stenosis, subaortic membrane, and aortic stenosis. Given the importance of maintaining sinus rhythm and preserving the “atrial kick” in patients with congenital heart disease, ablation therapy should be strongly considered as Class IC and III antiarrhythmic drugs have limited efficacy.

Anticoagulation is advised for patients with atrial tachyarrhythmia to reduce the thromboembolic risk. There is a lower threshold for full anticoagulation in the congenital heart disease population than predicted with the application of the CHA2DS2-VASc, as the ACHD population is younger and commonly lacks the traditional cardiovascular risk factors (eg, diabetes, hypertension, coronary artery disease).

Ventricular arrhythmia and the risk of sudden cardiac death (SCD) increase with age and congenital heart lesion complexity. Risk factors for SCD include prior SVT, increased QRS duration, and diminished systemic/subpulmonary ventricular function.10 The highest risk congenital cardiac lesions include single ventricles palliated with a Fontan circuit, Eisenmenger syndrome, repaired TOF, and Ebstein anomaly. Other lesions at increased risk of ventricular arrhythmia and SCD include uncorrected transposition of the great arteries (d-TGA) with surgical atrial switch and L-TGA in which the right ventricle is the systemic ventricle. It is reasonable to prescribe beta-blockers to patients with d-TGA postatrial switch and intra-atrial reentrant tachycardia to protect against ventricular arrhythmias and SCD.7 The relationship between QRS duration and its association with SCD (eg, QRS > 180 ms in repaired TOF) is regarded as an indirect assessment of right ventricular dysfunction for which surgical repair (eg, pulmonary valve replacement in TOF) may offer hemodynamic relief. However, it is unclear whether these surgical repairs eliminate the future arrhythmic risk. Drug therapy for ventricular arrhythmias in these patients includes beta-blockers and Class III antiarrhythmic drugs—with amiodarone being the mainstay—typically used in conjunction with an automatic implantable cardioverter defibrillator (AICD) device according to practice guidelines. Antiarrhythmic drugs may be helpful in reducing recurrent AICD discharges, and radiofrequency ablation of ventricular arrhythmia has also shown promise.

Importantly, while medical and invasive options for treating arrhythmias are available, new arrhythmias in the ACHD population should prompt an assessment of hemodynamics and new structural disease.


ACHD may require anticoagulation or antiplatelet therapy for a variety of reasons, including risk or evidence of thromboembolism, atrial arrhythmia, ventricular dysfunction, mechanical valve replacement, and temporarily after shunt closure.1 Atrial fibrillation, Fontan circulation, and CHA2DS2-VASc score greater than or equal to 1 are the most common reasons ACHD patients receive systemic anticoagulation.11

Per ACC/AHA 2020 guidelines, patients with bioprosthetic valves should receive aspirin lifelong if there is not an indication for other anticoagulation. Aspirin combined with vitamin K antagonists (VKA, ie, warfarin) is a IIb recommendation for mechanical valves.12 The role of aspirin in the prevention of endocarditis or its embolic complications has not been established,13 yet animal models suggest aspirin may inhibit fibrin and microthrombi formation that are the initial nidus for vegetations.14

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May 8, 2022 | Posted by in CARDIOLOGY | Comments Off on Pharmacologic Therapy for Adult Congenital Heart Disease

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