American Journal of Therapeutics 21, 325–326 (2014)
Digoxin Therapy for Atrial Fibrillation in the Twenty-First Century
Digitalis therapy for heart failure and atrial fibrillation has been around for a very long time. It was in 1785 that William Withering first introduced Digitalis therapy. Since its introduction, the drug from the Foxglove plant has been the center of repeated controversies. Those controversies all probably stem from the drug’s low therapeutic to toxic ratio of approximately two to one, an unheard of therapeutic margin in clinical therapeutics. When other physicians took up digitalis therapy, mortality was high on Harley Street and its use dwindled. Digoxin was introduced much later for heart failure and AF therapy in the U.S. and once again, its dangers were noted. In the last decade of the 20th century, much of the toxicity of digitalis therapy was attributed to its combined use with quinidine. Still the controversy surrounding the use of digitalis swells. Possibly compounding the questions of its appropriate use are the real differences among the digitalis preparations, with digoxin’s pharmaco-therapeutic action different from strophanthis and ouabain to mention but a few of the formulations no longer available in the U.S. The potential hazard of digoxin use in AF patients has recently been highlighted in a paper analyzing outcomes in 122,465 patients, a large sample indeed. In this report by Turakhia and associates from a Veteran’s Administration database, digoxin was associated with an increased risk of death in patients with newly diagnosed atrial fibrillation (AF). Considering that about 6.5 million patients receive digoxin, the observation, if true, is a major public health problem. The mortality difference between those taking digoxin and those not on digoxin was 95 vs. 67 per 1,000 patients. Thus for, 6.5 million patients (alibi the majority were probably receiving digoxin for CHF, not AF) that would amount to 18,200 excess deaths per year. This is not the first time digoxin’s use in AF therapy has been questioned by observational retrospective trials. About a year ago, two papers evaluated the use of digoxin in patients treated as part of the AFFIRM Trial that randomized 4,060 patients. One paper by Whitbeck and associates found digoxin was associated with a significant increase 1075–2765 Ó 2014 Lippincott Williams & Wilkins
in all-cause mortality in AF patients. Another analysis of the AFFIRM database found no such increased mortality. These two groups of investigators used very different analytical techniques. Whitbeck assessed digoxin’s potential toxicity in a time dependent manner (how long on digoxin), while Gheorghiade assessed digoxin at the time of randomization. Gheorghiade’s analysis had a selection bias issue and Whitbeck’s analysis an indication bias. Gheorghiade could not evaluate many patients due to insufficient data, while the development of heart failure and patient deterioration over time could not be well accounted for in the Whitbeck analysis. Perhaps the most critical problem with all these studies is that the assessment is retrospective, nonrandomized. Despite trying to adjust for the severity of the illness and the severity of heart failure, all critical contributors to outcome and important interacting factors with digoxin’s potential adversity. We know from multiple animal studies and clinical data that heart failure, ischemia, myocardial infraction, alone or in combination, can lower the therapeutic to toxic ratio of digoxin, increasing mortality. In the Turakhia report, only 23% of patients eligible for digoxin therapy received digoxin. What were the factors employed in the digoxin selection process. Often physicians chose to use digoxin for rate control when the patients also has heart failure. The Dig Trial did find that digoxin therapy significantly reduced heart failure admissions and this is often part of the physician’s decision process of employing digoxin for rate control when heart failure is also present. In the Turakhia report, 21% of patients receiving digoxin had congestive heart failure (CHF) while only 14% of those not receiving digoxin had CHF, P , 0.001. Despite sophisticated statistical methods, there is no substitution for randomization to correct for selection bias on the part of treating physicians. In fact, this is not bias, but the use of clinical judgment. Using digoxin only for rate control in heart failure patients where physicians consider the risk of digoxin appropriate, since it helps in rate control and reduces heart failure re-hospitalization. www.americantherapeutics.com
326
In many of the news reports, both physicians and the lay public are quoted as suggesting using alternative therapies. However, the safety of alternative therapies are also not well established in terms of mortality outcome. What we need is a controlled perspective randomized trial evaluating AF therapy and especially the safety
American Journal of Therapeutics (2014) 21(5)
Somberg
and therapeutic benefit of digoxin. Even a trial like this would not evaluate alterative digitalis therapies and thus possible benefit of other shades of purple. John C. Somberg, MD Editor
www.americantherapeutics.com
Digoxin Therapy for Atrial Fibrillation in the Twenty-First Century
Digitalis therapy for heart failure and atrial fibrillation has been around for a very long time. It was in 1785 that William Withering first introduced Digitalis therapy. Since its introduction, the drug from the Foxglove plant has been the center of repeated controversies. Those controversies all probably stem from the drug’s low therapeutic to toxic ratio of approximately two to one, an unheard of therapeutic margin in clinical therapeutics. When other physicians took up digitalis therapy, mortality was high on Harley Street and its use dwindled. Digoxin was introduced much later for heart failure and AF therapy in the U.S. and once again, its dangers were noted. In the last decade of the 20th century, much of the toxicity of digitalis therapy was attributed to its combined use with quinidine. Still the controversy surrounding the use of digitalis swells. Possibly compounding the questions of its appropriate use are the real differences among the digitalis preparations, with digoxin’s pharmaco-therapeutic action different from strophanthis and ouabain to mention but a few of the formulations no longer available in the U.S. The potential hazard of digoxin use in AF patients has recently been highlighted in a paper analyzing outcomes in 122,465 patients, a large sample indeed. In this report by Turakhia and associates from a Veteran’s Administration database, digoxin was associated with an increased risk of death in patients with newly diagnosed atrial fibrillation (AF). Considering that about 6.5 million patients receive digoxin, the observation, if true, is a major public health problem. The mortality difference between those taking digoxin and those not on digoxin was 95 vs. 67 per 1,000 patients. Thus for, 6.5 million patients (alibi the majority were probably receiving digoxin for CHF, not AF) that would amount to 18,200 excess deaths per year. This is not the first time digoxin’s use in AF therapy has been questioned by observational retrospective trials. About a year ago, two papers evaluated the use of digoxin in patients treated as part of the AFFIRM Trial that randomized 4,060 patients. One paper by Whitbeck and associates found digoxin was associated with a significant increase 1075–2765 Ó 2014 Lippincott Williams & Wilkins
in all-cause mortality in AF patients. Another analysis of the AFFIRM database found no such increased mortality. These two groups of investigators used very different analytical techniques. Whitbeck assessed digoxin’s potential toxicity in a time dependent manner (how long on digoxin), while Gheorghiade assessed digoxin at the time of randomization. Gheorghiade’s analysis had a selection bias issue and Whitbeck’s analysis an indication bias. Gheorghiade could not evaluate many patients due to insufficient data, while the development of heart failure and patient deterioration over time could not be well accounted for in the Whitbeck analysis. Perhaps the most critical problem with all these studies is that the assessment is retrospective, nonrandomized. Despite trying to adjust for the severity of the illness and the severity of heart failure, all critical contributors to outcome and important interacting factors with digoxin’s potential adversity. We know from multiple animal studies and clinical data that heart failure, ischemia, myocardial infraction, alone or in combination, can lower the therapeutic to toxic ratio of digoxin, increasing mortality. In the Turakhia report, only 23% of patients eligible for digoxin therapy received digoxin. What were the factors employed in the digoxin selection process. Often physicians chose to use digoxin for rate control when the patients also has heart failure. The Dig Trial did find that digoxin therapy significantly reduced heart failure admissions and this is often part of the physician’s decision process of employing digoxin for rate control when heart failure is also present. In the Turakhia report, 21% of patients receiving digoxin had congestive heart failure (CHF) while only 14% of those not receiving digoxin had CHF, P , 0.001. Despite sophisticated statistical methods, there is no substitution for randomization to correct for selection bias on the part of treating physicians. In fact, this is not bias, but the use of clinical judgment. Using digoxin only for rate control in heart failure patients where physicians consider the risk of digoxin appropriate, since it helps in rate control and reduces heart failure re-hospitalization. www.americantherapeutics.com
326
In many of the news reports, both physicians and the lay public are quoted as suggesting using alternative therapies. However, the safety of alternative therapies are also not well established in terms of mortality outcome. What we need is a controlled perspective randomized trial evaluating AF therapy and especially the safety
American Journal of Therapeutics (2014) 21(5)
Somberg
and therapeutic benefit of digoxin. Even a trial like this would not evaluate alterative digitalis therapies and thus possible benefit of other shades of purple. John C. Somberg, MD Editor
www.americantherapeutics.com
