PubMed · 5705080
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J Dall. 1968. Digitalis toxicity.. https://pubmed.ncbi.nlm.nih.gov/5705080/
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The Digitalis Investigation Group (DIG) trial was a randomized, double-blind placebo-controlled trial whose primary objective was to determine whether digoxin had beneficial, harmful, or no effect on total mortality in patients with heart failure who were in sinus rhythm and whose ejection fraction was </=0.45. The study was designed as a large simple trial with a large number of centers (302) in the United States and Canada, many of which were inexperienced in research. To ensure that the results of the trial would be reported accurately without possible bias due to missing data, the study leadership decided that no outcome results would be reported until the vital status at the end of the study was known for at least 97% of the study participants. Planning for closeout of the study began a year prior to the common end date of December 31, 1995 and included plans for obtaining vital status on December 31, 1995. Participants were given postcards at their final study visit to be completed and mailed on or after January 1, 1996. Of 5602 postcards distributed, 5070 (90.5%) were completed and returned. A contract search agency was hired to locate the remaining participants. Of the total 7788 participants entered into the DIG trial, only 97 participants (1.2%) could not have their vital status as of December 31, 1995 determined. It is recommended that investigators having an outcome measure with a common end date include plans in their protocols for obtaining their measures and activate those plans as early as possible during the course of the study.
Cardiac glycosides have played a prominent role in the therapy of congestive heart failure since William Withering codified their use in his late 18th century monograph on the efficacy of the leaves of the common foxglove plant (Digitalis purpurea). Despite their widespread acceptance into medical practice in the ensuing 200 years, both the efficacy and the safety of this class of drugs continue to be a topic of debate. Moreover, despite the fact that the molecular target for the cardiac glycosides, the alpha-subunit of sarcolemmal Na+K+-ATPase (or sodium pump) found on most eukaryotic cell membranes, has been known for several decades, it remains controversial whether the sympatholytic or positive inotropic effects of these agents is the mechanism most relevant to relief of heart failure symptoms in humans with systolic ventricular dysfunction. Herein, we review the molecular and clinical pharmacology of this venerable class of drugs, as well as the manifestations of digitalis toxicity and their treatment. We also review in some detail recent clinical trials designed to examine the efficacy of these drugs in heart failure, with a focus on the Digoxin Investigation Group data set. Although, in our opinion, the data on balance warrant the continued use of these drugs for the treatment of symptoms of heart failure in patients already receiving contemporary multidrug therapy for this disease, the use of digitalis preparations will inevitably decline with the maturation of newer pharmacotherapies.
Angiotensin-converting-enzyme inhibitors increase life expectancy in congestive heart failure, and they have thus changed the therapeutic strategy. The well tolerated highest daily dosage has to be used. Diuretics are often associated with vasodilators; however, they have to be administered at a minimal chronic daily dosage, in order to avoid deleterious neurohormonal effects. Digoxin keeps a great interest, as the unique positive inotropic agent without surmortality. Nitrates associated or not with hydralazine may show an additional interesting benefit. The role of other vasodilators, namely amlodipine and losartan, in the treatment of chronic heart failure remains to be defined. New vasodilators are in development and might further increase our therapeutic possibilities against congestive heart failure.