The skeptical cardiologist is fascinated by the cardiac drug digoxin and the plant from which it is derived, the foxglove.
I wrote about “foxglove equipoise” in a previous post, touching on the contributions of William Withering in the 1700s, to understanding the toxicity and therapeutic benefits of the foxglove, and more recent concerns that digoxin increases mortality in patients with heart failure.
At the American College of Cardiology Scientific Sessions in Washington, D.C. yesterday, a paper showing higher mortality for patients on digoxin may be the final nail in the foxglove coffin.
Despite lack of evidence for its safety in the treatment of atrial fibrillation from randomized trials, digoxin is used in 30% of patients with atrial fibrillation (AF) worldwide, and current AF guidelines recommend it for rate control in patients with AF (with and without heart failure).
The investigators used data from the ARISTOTLE study of apixiban versus warfarin for their analysis.
They looked at mortality in patients taking or not taking digoxin at baseline, using a Cox model with propensity weighting, which included demographic features as well as biomarkers and digoxin levels at baseline. Major findings:
-In patients already taking digoxin, mortality was not higher in digoxin users, however, the risk of death was related to dig levels: for every 0.5 ng/ml increase in dig level, the risk of death rose by 19 percent and if dig level was >1.2 ng/ml the death rate increased by 56 percent.
–Patients not taking digoxin before the trial who began taking it over the course of the study had a 78 percent increase in the risk of death from any cause and a four-fold increased risk of sudden death after starting digoxin use. Most sudden deaths occurred within six months after digoxin was started.
–Risk of death with initiation of digoxin was increased in patients with and without heart failure.
The use of foxglove to treat dropsy is a fascinating and instructive chapter in the history of medicine.
This study added to prior systematic reviews suggests that it is time to end the use of digitalis and close the chapter.
William Withering might turn over in his grave but at least we won’t be sending afib patients to join him prematurely!
The skeptical cardiologist was born in Wrexham, North Wales, not too far from the northern area in Wales known as Snowdonia, the ancestral lands of the great Princes of Wales.
I’ve been back to this wonderful area several times in the last dozen years, entranced by its beauty and connection with my ancestor, Prince Llewelyn the Great.
Most recently I stayed in Beddgelert, a small village nestled at the base of Mount Snowdon, which , according to (possibly tourism-inspired) legend, is named after the grave of Gelert, the faithful hound of Prince Llewelyn.
A brief hike along the gurgling Glaslyn river takes you to a stone monument with these words inscribed:
“In the 13th century Llewelyn, prince of North Wales, had a palace at Beddgelert. One day he went hunting without Gelert, ‘The Faithful Hound’, who was unaccountably absent. On Llewelyn’s return the truant, stained and smeared with blood, joyfully sprang to meet his master. The prince alarmed hastened to find his son, and saw the infant’s cot empty, the bedclothes and floor covered with blood. The frantic father plunged his sword into the hound’s side, thinking it had killed his heir. The dog’s dying yell was answered by a child’s cry. Llewelyn searched and discovered his boy unharmed, but nearby lay the body of a mighty wolf which Gelert had slain.
The prince filled with remorse is said never to have smiled again. He buried Gelert here”.
While lingering in the little stone wall enclosure within which a statue of the faithful Gelert stood I espied a plant that looked like digitalis purpurea, more commonly known as foxglove.
Moving closer, I realized that I had indeed come face to face with a wildly growing foxglove, the plant that William Withering had utilized to treat patients with dropsy in the late -1700s.
I was understandably ecstatic as I was on a sort of mission to observe foxglove in its native environs. I had expected to view the medicinal plant in Shropshire where William Withering was born and where he had encountered “the old woman of Shropshire” who first inspired him to use foxglove for dropsy.
This unexpected foxglove experience seemed like a serendipitous harbinger of wonderful Witheringesque experiences to come.
Sure enough as we left the fog-enshrouded mountains of Snowdonia and drove on the left side of narrow, winding Welsh roads toward Shropshire we spotted a multiple large patches of wildly growing foxglove in a nearby meadow.
Although my children were eager to taste the foxglove and see if the inotropic properties of the digitalis within would make their hearts beat stronger and make them more powerful, I restrained them, for Withering’s writings and subsequent years of clinical experience with digitalis tell us that the therapeutic window is narrow and toxicity manifested by nausea and vomiting common.
It’s not a word I hear outside of medical circles but it serves a great function in the clinical arena.
When used in medicine as in the phrase “clinical equipoise” it means that medical experts are uncertain as to whether a treatment for a disease is helpful.
Thus, for digoxin, a drug which has been utilized for patients with heart failure or atrial fibrillation for 240 years, we still don’t know if the benefits outweigh the risks.
Digoxin is the major medicinally active chemical in the foxglove plant which was first described by Leonhart Fuchs (the plant and color fuchsia are named after him), a German botanist and physician in 1542. It was given the latin name digitalis purpurea, reflecting the plant’s purplish color and similarity to a thimble (German finger hut).
A vague understanding that the foxglove had medicinal and toxic properties existed in subsequent centuries, but it took a very observant physician from the West of England, William Withering, to give it a sold footing in the medical pharmacopeia.
Withering collected 10 years of his observations, using various preparations of foxglove to treat various diseases including the mysterious “dropsy” in the (now famous) An Account of the Foxglove and some of its Medical Uses.”
He writes of his rationale for beginning to give patients foxglove:
“In the year 1775, my opinion was asked concerning a family receipt for the cure of the dropsy. I was told that it had long been kept a secret by an old woman in Shropshire who had sometimes made cures after the more regular practitioners had failed. I was informed also, that the effects produced were violent vomiting and purging; for the diuretic effects seemed to have been overlooked. This medicine was composed of twenty or more different herbs; but it was not very difficult for one conversant in these subjects, to perceive, that the active herb could be no other than the Foxglove.”
Dropsy was that era’s term for edema: “The dropsy is a preternatural swelling of the whole body, or some part of it, occasioned by a collection of watery humour. It is distinguished by different names, according to the part affected, as the anasarca, or a collection of water under the skin; the ascites, or a collection of water in the belly; the hydrops pectoris, or dropsy of the breast; the hydrocephalus, or dropsy of the brain, &c. [Buchan1785].”
Foxglove was in clinical equipoise in 1775. When Withering started giving it to his patients with dropsy he did not know if it would help or harm them.
After trying various preparations of the foxglove in varying dosages in hundreds of patients he concluded that it was of a great benefit as long as it was carefully titrated to avoid the toxicities of overly slow pulse and vomiting.
With modern medicines that are proven to be safe and effective we demand evidence from randomized controlled trials in which the active drug is compared to a placebo. There are too many factors which affect the course of a disease to accept the kind of observational evidence that Withering collected.
Digitalis is currently utilized in heart failure and atrial fibrillation. Withering’s patients likely had one or both of these conditions.
A recent observational study found that digitalis usage in patients with newly diagnosed atrial fibrillation was associated with a 26% higher risk of dying.
The only large randomized trial of digoxin, the DIG (Digitalis Investigation Group) trial, showed no effect on mortality, but digoxin did reduce hospitalization among patients with heart failure and a reduced ejection fraction (HFrEF)
The DIG study was performed in the early 1990s, before current optimal treatment regiments for heart failure with reduced ejection fraction were developed and may no longer relevant. More recent observational studies suggest digoxin raises mortality in heart failure.
Thus, the foxglove or digitalis, although used for 240 years in hundreds of thousands of patients for both heart failure and atrial fibrillation remains in clinical equipoise.
Doctors must be very circumspect in prescribing this medicine. Personally, I do not use digoxin in heart failure patients.
I use digoxin in chronic atrial fibrillation only as a last resort when other agents do not allow adequate slowing of the heart rate and I carefully monitor levels and kidney function if a patient is on it.
I have, however, decided to start growing foxglove in my garden. I will try to warn the ducks, rabbits and squirrels not to partake of its beautiful flowers as they might prove deadly.
I also plan to visit the grave of Withering on my upcoming trip to Europe, for upon his tombstone it is said, there is an engraving of the foxglove!