Is Antiarrhythmic Treatment in the Elderly Different?

Abstract

Aging is associated with electrical and structural changes of the myocardium. The response to catecholamines is also reduced and the baroreceptor reflex activity is blunted. These aspects conceivably affect the response to antiarrhythmic drugs in the elderly. Furthermore, physiological parameters change in older age, affecting the pharmacokinetics of drugs. In this article, the literature on the pharmacokinetics and pharmacodynamics of antiarrhythmic drugs in elderly subjects is reviewed with the purpose of improving their optimal and safe prescription.

Pharmacokinetic studies of antiarrhythmic drugs in the elderly are sparse, and there are no data available for procainamide and propafenone. Mean dose reductions calculated for elderly patients relative to younger patients are 60% for digoxin, 19% for diltiazem, 32% for disopyramide, 31% for flecainide, 40% for metoprolol, 35% for quinidine, 29% for sotalol and 26% for verapamil. No dose reductions are required for dofetilide or dronedarone. The clearance of dofetilide is not affected by age after correction for renal function. The dosage of dofetilide is individualized according to an algorithm based on the corrected QT (QTc) interval and renal function. Although the area under the plasma concentration-time curve (AUC) for dronedarone is larger in elderly patients, the dose should not be reduced because the registered dose has specifically been studied in an elderly population. In elderly patients with renal insufficiency, hepatic impairment, heart failure or certain genetic variants, the pharmacokinetics of antiarrhythmic drugs might be affected to an even greater extent, meaning additional dosage adjustments are necessary.

With increasing age, the number of prescribed drugs increases because of co-morbidity, making interactions between drugs more likely. Several drugs interact with antiarrhythmic drugs, leading to clinically relevant changes in drug concentrations or AUC values. Furthermore, several drugs with non-cardiovascular indications appear to have QTc prolonging effects. The combination of these drugs with antiarrhythmic drugs that affect the QTc interval increases the risk of developing torsades de pointes and should therefore be avoided.

Altered effects of drugs in the elderly can also be the result of age-related changes in the cardiovascular system. For example, atenolol and sotalol show greater effects, i.e. reductions in heart rate and increased probability of adverse effects, at a given plasma concentration in older subjects compared with younger subjects.

It remains unclear whether old age as such is a determinant for reduced or modified efficacy of antiarrhythmic drugs. In a randomized study it was found that patients aged ≥65 years with atrial fibrillation had better survival with rate control than with rhythm control. However, different treatment strategies were compared and the results cannot be extrapolated to indicate better survival with a specific antiarrhythmic drug.

Antiarrhythmic drugs will remain the first-line approach in most patients for the prevention or suppression of atrial and ventricular arrhythmias. As a rule of thumb, a 50% reduction in the starting dose of antiarrhythmic drugs compared with younger patients appears a wise approach in elderly patients. However, this does not apply to dofetilide and dronedarone. The selection of antiarrhythmic drugs in the elderly is predominantly determined by factors such as the treatment target, assumed patient compliance, possible drug interactions, co-morbidity, and renal and liver function. Efficacy and safety monitoring should take into account symptoms, ECG findings, rhythm recordings, plasma drug concentrations and other laboratory parameters.

Appendices

Appendices

Appendix A

Calculation of Creatinine Clearance

The extent to which renal function is decreased can be estimated by measuring serum creatinine and calculating the creatinine clearance by the Cockcroft and Gault equation (equation 1). This equation can be used in the setting of stable kidney function.

Cockcroft and Gault equation:

$$\matrix{{{\rm{For\;male\;patients:}}} \cr {{\rm{Creatinine\;clearance}}[{\rm{mL}}/\min ] = {{(140 - {\rm{age}}[{\rm{y}}]) \times {\rm{bodyweight}}[{\rm{kg}}]} \over {0.815 \times {\rm{serum\;creatinine}}[\mu {\rm{mol}}/{\rm{L}}]}}} \cr {{\rm{For\;female\;patients}}:} \cr {{\rm{Creatinine\;clearance}}[{\rm{mL}}/\min ] = {\rm{as\;for\;male\;patients\;but\;multiplied\;by\;a\;factor\;of}}0.85} \cr }$$

((Eq. 1))

Appendix B

Example of Calculation ofSotalol Clearance in Renal Insufficiency and Calculation of Dosage Adjustment

From the study of Ishizaki et al.,[34] it can be extrapolated from the sotalol specific model that (equation 2):

$${\rm{Sotalol\;total\;clearance}}[{\rm{mL}}/\min ] = 84.7[{\rm{mL}}/\min ] + 2 \times {\rm{creatinine\;clearance}}[{\rm{mL}}/\min ]$$

((Eq. 2))

Thus, in a patient with a creatinine clearance of 30 mL/min, the sotalol clearance is (equation 3):

$$\matrix{{{\rm{Sotalol\;total\;clearance}}[{\rm{mL}}/\min ]} \cr { = 84.7[{\rm{mL}}/\min ] + 2 \times 30[{\rm{mL}}/\min ]} \cr { = 145\;{\rm{mL}}/\min } \cr }$$

((Eq. 3))

From the study of Ishizaki et al.,[34] it can be extrapolated that sotalol total clearance in healthy subjects is 377 mL/min, based on the reported mean clearance and mean bodyweight of healthy subjects.

Similar to the equation in Appendix D that calculates dose adjustments based on clearance data for elderly versus young patients, the dose adjustment can be calculated as follows (equation 4):

$$\matrix{{{\rm{Dose\;adjustmen}}{{\rm{t}}_{{\rm{renal}}\_{\rm{insufficiency}}}}[\% ]} \cr { = (1 - {\rm{clearanc}}{{\rm{e}}_{{\rm{renal}}\_{\rm{insufficiency}}}}/{\rm{clearanc}}{{\rm{e}}_{{\rm{healthy}}}}) \times 100\% } \cr { = (1 - 145/377) \times 100\% } \cr { = 62\% } \cr }$$

((Eq. 4))

Appendix C

Area under the Plasma Concentration-Time Curve

The area under the plasma concentration-time curve (AUC) [see figure A1, grey-shaded area] is a measure of the systemic exposure to a particular drug. For example, if the drug displays linear pharmacokinetics, a 50% reduction in clearance will result in a 2-fold increase in the AUC.

Fig. A1

Area under the plasma concentration-time curve after ingestion of an oral formulation of the drug.

Appendix D

Calculation of Dose Adjustments

The following formulas were used to calculate dose adjustments (equations 5 and 6):

$${\rm{Dose\;adjustmen}}{{\rm{t}}_{{\rm{elderly}}}}[\% ] = (1 - {\rm{clearanc}}{{\rm{e}}_{{\rm{elderly}}}}/{\rm{clearanc}}{{\rm{e}}_{{\rm{young}}}}) \times 100\% $$

((Eq. 5))

$${\rm{Dose\;adjustmen}}{{\rm{t}}_{{\rm{elderly}}}}[\% ] = (1 - {\rm{AU}}{{\rm{C}}_{{\rm{young}}}}/{\rm{AU}}{{\rm{C}}_{{\rm{elderly}}}}) \times 100\% $$

((Eq. 6))

For equation 6, if applicable, area under the plasma concentration-time curve (AUC) values can be replaced by plasma concentration data.