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We appreciate Dr. Krohn’s interest and comments concerning our analysis. We believe our conclusions as stated in the study are correct. While it is true that the serum digoxin concentration (SDC) is significantly higher than the tissue concentration during the distributive phase of digoxin dosing (6 to 12 h), both the SDC and the amount of drug in the body decline in parallel and are directly related 12 to 24 h post-dose (1). This is the rationale for the recommendation to always draw the SDC as a trough concentration—that is, 24 h after the dose (2). This was mandated in both the PROVED and RADIANCE protocols.
We agree with Dr. Krohn’s statement that total body stores of digoxin are easy to calculate. Unfortunately, we are unable to do this for each individual patient in these studies. However, the dosing guidelines cited by Dr. Krohn are incorporated into the dosing table that is currently included in the Lanoxin package insert (2). A similar strategy was used in the PROVED, RADIANCE, and DIG studies, which produced mean SDCs in the range of 0.9 to 1.2 ng/ml. We also agree that the current therapeutic range for digoxin (0.8 to 2.0 ng/ml) is poorly defined and is based primarily on toxicity—not efficacy. As Dr. Krohn states, some patients may have high concentrations (>2.0 ng/ml) without evidence of toxicity, whereas others may have relatively low concentrations and demonstrate efficacy, a point we are attempting to make with our study. However, it is clear that, in general, the higher the concentration, the greater the risk for toxicity. Our analysis, within the limitations indicated, finds no evidence for a relationship between serum concentration and efficacy. Patients who continued digoxin, including those with a low SDC, did better than those who had it withdrawn. Because lower SDCs appear to be effective, toxicity can be minimized with a low dose of digoxin while preserving clinical benefit.
Finally, Dr. Krohn notes the high doses of digoxin used for the acute management of supraventricular arrhythmias postoperatively, whereas our analysis focuses on the outpatient management of patients with chronic heart failure. We would suggest that, for a number of reasons (age, left ventricular function, renal function, etc.), these may be two totally different patient populations. Their handling of digoxin, requirement of higher SDC, and ability to tolerate a higher SDC may differ as well. Perhaps the most important point is that the SDC should not serve as the sole marker for efficacy or toxicity but should be taken into consideration along with the patient’s clinical information. The dose and SDC should always be individualized for any given patient.
Optimal dosing remains a vital but relatively poorly studied aspect of cardiovascular therapeutics. We believe our work provides useful data concerning dosing of digoxin, a medication that remains among the most commonly prescribed worldwide for heart failure.
- American College of Cardiology Foundation