Digitalis Investigation Group (DIG) trial: A stimulus for further research☆,☆☆,★

Mechanism and Dose Response

The results of the DIG trial should prompt us to critically reexamine what we know about the mechanisms of digoxin, its dose response, and drug interactions to see if there are any possibilities to maintain its beneficial effects while increasing its safety.

Digoxin has a positive inotropic effect that is related to its ability to inhibit the sodium-potassium adenosine triphosphatase (ATP-ase). 25, 26 The inhibition of sodium-potassium ATP-ase in the sarcolemma membrane of the cardiac myocytes

Improving the Safety of Digoxin

Several drugs such as quinidine, 93, 94, 95, 96 verapamil, ⁹⁷ amiodarone, ⁹⁸ and clarithromycin 99, 100 have been shown to increase serum digoxin concentration and the likelihood of digitalis intoxication. In view of the uncertainty regarding the benefits and risks of high-dose digoxin and the failure to show a survival advantage of digoxin in the DIG trial, careful attention should be paid to concomitant medications, and the serum digoxin concentration should be checked and adjusted when one

Digoxin in Heart Failure From Coronary Artery Disease Versus Primary Cardiomyopathy

The Veterans Affairs trial on amiodarone suggests that the cause of heart failure may influence the efficacy of a drug because only patients with heart failure not from myocardial ischemia seem to derive a benefit from the drug. ¹³⁰ The Cardiac Insufficiency Bisoprolol Study (CIBIS) found no significant reduction with the β-blocker bisoprolol in patients with ischemic heart failure but did find a benefit in those with nonischemic heart failure. 117, 131 In the recent Prospective Randomized

Conclusion

Regardless of the approach eventually chosen, the most important implication of the DIG trial may not be for current practice but rather as a stimulus for further basic and clinical research in an attempt to maintain or enhance the beneficial effects of digoxin on preventing progressive heart failure while decreasing the potential for sudden cardiac death. These efforts should be pursued in view of the fact that there are more than 24 million prescriptions written for this drug every year; the