Paul D. Thompson, MD

A new clinical trial (1) and the accompanying clinical commentary (2) suggest that digoxin may be coming back from the dead.

The Rate control Therapy Evaluation in permanent Atrial Fibrillation trial (RATE–AF) was an open-label, but endpoint-blinded study that assigned 160 patients, aged 60 or older with permanent atrial fibrillation (AF) to treatment with either digoxin or bisoprolol.

 Patients had New York Heart Association Class II or greater heart failure.

The primary outcome was quality of life (QOL) assessed by questionnaire at 6 and 12 months; there were 17-20 secondary endpoints. Neither QOL nor 16 of 17 secondary parameters were different at 6 months, although more digoxin-treated patients improved their European Heart Rhythm Association symptom classification score 2 or more classes (53 vs 9%, 

At 12 months, 8 of 20 secondary outcomes improved more with digoxin than with bisoprolol, including NTproBNP (960 vs 1250 pg/mL in the two groups, respectively). Serious adverse events occurred in 37 of the bisoprolol, but in only 15 of the digoxin patients. Heart rates did not differ.

 with these results! I had never totally abandoned digoxin, partly because when I was trained in the 1970s, digoxin was 

 drug for AF rate control. But I constantly doubted my continued use. That’s because a series of cross-sectional studies showed worse clinical outcomes in acute MI patients treated with digoxin.

These studies and the accompanying editorials left the drug for dead. I vaguely remember one academic electrophysiologist editorializing that use of digoxin was essentially malpractice. I dismissed these results and editorials by arguing that patients who received digoxin did so because they were sicker and developed AF. The TREAT-AF study, however, was a controlled study that showed increased mortality in digoxin treated patients, but this was not a true randomized controlled clinical trial because it used propensity matching to create the control group.

I stuck with digoxin over the years—not for everybody, but for those AF patients whose rates were difficult to control. Most patients with atrial arrhythmias can be controlled with beta-blockers or calcium channel blockers alone, but some with AF, and many with atrial flutter, require either high drug doses or an additional agent.

Beta-blockers block adrenergic stimulation, which is actually not great at rest and increases with exertion. In contrast, digoxin increases vagal tone, meaning that its greatest effect is on resting heart rate—when vagal tone is greatest. Consequently, combining digoxin with moderate doses of beta-blockers provides both resting and exercise AF rate control.

Also, one of the biggest hassles I get with beta-blockers is that the nurses hold the drug because the patient is hypotensive. Actually, most often the patient is hypotensive because their AF rate is too fast. Fast heart rates decrease filling time, leading to low stroke volumes and low systolic pressures.

Slowing the heart rate often cures the hypotension, but I have become hoarse trying to change nurses’ minds on this issue. Digoxin has saved my voice because it does not get held anywhere near as frequently as beta- or calcium channel blockers, but I always get pushback from the new cardiology fellows when I suggest using digoxin. This resistance usually dissipates after they see how well it works.

So, here are my suggestions for using digoxin effectively:

Always load the patient. Digoxin like many anti-arrhythmics does almost nothing without fully loading the patient. I load small-bodied patients with 0.25 mg IV x 3 doses given every hour or even faster if rate control requires faster dosing. I load large patients with 0.25 mg IV x 4 doses every hour. I look at the patient to decide who is small and who is large. I load outpatients using similar doses given orally.

Start hospitalized patients with intravenous digoxin so that whether it will work is prompt and obvious.

Do not worry about renal function when loading patients. Renal function affects digoxin clearance and therefore the replacement dose but not the loading dose. Normally, one-third of digoxin is cleared with normal kidney function so the maintenance dose is usually 0.25 mg or one-third of the loading dose. Lower maintenance doses are required with decreased renal function.

Do not use digoxin levels to evaluate the drug’s effectiveness. Digoxin level tells you only if the patient has taken the drug and if the blood concentration exceeds a safe level and you need to cut the dose. Increase the dose if the heart rate is not controlled and the dig level is not excessive.

I think that many inexpensive, useful drugs get abandoned because there is no industry push to use them. Others are victims of poor study designs, often industry-sponsored trials designed to make the generic drug look bad. None of the AF guidelines list digoxin as first-line therapy because there are no true RCCTs of digoxin.

 RATE-AF is not a perfect RCCT because it was open-labeled but hopefully it will prompt a closer look at this 235-year-old drug.

Kotecha D, Bunting KV , Gill, SK, et al. 

Effect of Digoxin vs Bisoprolol for Heart Rate Control in Atrial Fibrillation on Patient-Reported Quality of Life: The RATE-AF Randomized Clinical Trial

Curfman G. Digitalis Glycosides for Heart Rate Control in Atrial Fibrillation. JAMA. 2020 Dec 22;324(24):2508

Articles

In this column, Dr. Paul Thompson offers his perspective on the use of digoxin and explains why he has maintained use in certain patient populations despite its waning popularity in recent years.

Paul D. Thompson, MD: Is Digoxin Back from the Dead?

I was never in the military not because I had dangerous heel spurs—thank goodness—but because I had a medical school deferment. I do know enough about the military, however, to know that you can follow a person’s military career from the services ribbons mounted on the left chest of his/her dress uniform. These service ribbons provide us much more information than a person’s “name, rank and serial number”.

I am lucky enough to spend one week a month rounding with trainees in Boston. I recently observed an excellent MD/PhD resident interview a new patient. We left that patient’s room with a complete past and present medical history, but we also left not knowing 

 the patient was. He was in a hospital gown so we had literally, and now figuratively, taken away his clothes and his personal identity.

I call finding out who a patient is, what they do, and where they live “giving them back their clothes”. It is really giving them back their personal identity, and it’s critically important. Not because it’s politically correct, but because if patients know that you are as interested in them as you are in their disease, they are more likely to ask questions, reveal their wants and worries, and participate fully in their care by taking their medicines and following your advice. And me? I get to develop relationships with patients and learn about their lives, something that brought most of us into medicine in the first place.

In this column, titled "Give Them Back Their Clothes", Dr. Paul Thompson reflects on the importance of creating a personal connection with patients as part of their care routine and the impact it can have on patients. 

Compassion in Medicine: Give Them Back Their Clothes

“Diagnostic anchoring” refers to clinicians’ tendency to make a diagnosis and to avoid considering the alternatives. I have had several patients referred to me over my career with the diagnosis of hypertrophic cardiomyopathy (HCM), who turned out to have cardiac amyloidosis. Amyloidosis and other diseases that produce left ventricular hypertrophy (LVH) are called “HCM phenocopies” because they copy the HCM phenotype but do not have the genotype.

Recognizing HCM phenocopies, and not succumbing to diagnostic anchoring, is now critically important because there are new treatments for some HCM phenocopies that can prevent progression and even initiate regression of the non-HCM disease. The following is a compilation of what I knew about this topic plus material presented in a web-based lecture on November 20, 2020, entitled “Highlighting Hypertrophic Cardiomyopathy and Fabry Cardiac Disease”.

The differential diagnosis of a thick heart includes classical HCM, long-standing poorly treated hypertension, cardiac amyloidosis, alpha-galactosidase A (a-GSA) deficiency or Fabry disease, lysosomal associated membrane protein–2 deficiency (LAMP-2) also called Danon or LAMP-2 disease, and hydroxychloroquine (HCQ) treatment.

HCM is the most frequent cause of thick hearts and affects 1/250 individuals.HCM is autosomal dominant and not sex-linked. It typically produces more septal than other wall hypertrophy. Indeed, HCM was historically called asymmetric septal hypertrophy or ASH. Clinicians should consider diagnoses other than HCM if there is no family history of HCM, when the disease onset is late in life, and when there is symmetric LVH or LVH that does not include the septum. But be careful because if anything typifies HCM, it is its variability. HCM can produce apical and symmetrical LVH, appear late in life, and occur in non-inherited patterns. One notorious example of a non-inherited pattern involved a cluster of HCM patients due to sperm-donation from an undiagnosed HCM carrier! 

Long-standing, poorly treated hypertension (HBP) can cause LVH, but this is now a rare HCM mimic because HBP is usually diagnosed and treated before the LVH is extreme.

Cardiac amyloidosis is presently recognized more frequently as causing thick hearts because of increased awareness of the disease and the use of non-echo imaging techniques such as magnetic resonance imaging (cMRI) and technetium 99 pyrophosphate scanning. Amyloidosis comes in three varieties.

 Deposition of antibody light chains produces AL amyloidosis. These light chains are produced by clonal plasma cells so it is treated as a variant of multiple myeloma. Inherited transthyretin (TTR) amyloidosis is due to mutations in the TTR gene. A gene mutation is present in approximately 3% of African Americans, but mutations occur in other populations including the Irish. 

There is also a non-inherited or “wild type” (wt) TTR amyloidosis. TTR amyloidosis is more frequent in men, especially old men, despite not being sex-linked. TTR amyloidosis produces orthopedic issues such as biceps tendon ruptures, carpal tunnel symptoms, spinal stenosis, and palmar tendon nodules, which may appear years before the cardiac amyloidosis becomes obvious. Amyloidosis should also be considered in patients with LVH and peripheral neuropathy since amyloid also invades peripheral nerves. It is important to diagnose TTR amyloidosis because new treatments such as tafamidis can help preserve functional capacity and reduce cardiovascular mortality.

Interestingly, 20% of patients with wtTTR have asymmetric septal hypertrophy making wtTTR a worthy HCM phenocopy. 

Patients whose LVH is due to HCM and especially those whose LVH is due to HBP should have impressive voltage criteria for LVH whereas patients with amyloidosis have either normal or decreased LV voltage. But a history of HBP that has been mysteriously cured and no longer requires anti-HBP drugs suggests new peripheral neuropathy another symptom of amyloidosis.

Fabry disease is another treatable cause of thick hearts. Fabry is X-linked and results from a decrease in lysosomal a-GSA activity resulting in the accumulation of glycosphingolipids in lysosomes. About 0.03% of the population carries the Fabry gene. It usually produces concentric LVH with LGE of the posterior wall and, in contrast to HCM, spares the septum.

Fabry also can produce ascending aortic enlargement and aortic insufficiency. Fabry should be considered with late-onset LVH especially if there is aortic enlargement. The disease is more common and severe in men, because of the X-linked inheritance. This inheritance pattern means that men can be diagnosed by measuring serum a-GSA activity because they don’t produce any, but that women must have gene analysis to detect the genetic defect. Fabry also causes AV conduction disease. Even though Fabry usually causes diffuse LVH, it can produce septal hypertrophy ASH and even systolic anterior motion of the mitral valve so Fabry should be excluded in all thick hearts. Both enzyme replacement therapy and migalastat, which helps chaperone a-GSA to lysosomes, reduce LVH in Fabry.

Danon or LAMP-2 disease is another rare, X-linked lysosomal glycogen storage disease. It usually presents in children who also have muscle weakness and intellectual disability.

Finally, HCQ can also produce a lysosomal storage disorder that mimics HCM becauseHCQ inhibits lysosomal function.

 HCQ is no longer recommended for COVID-19 treatment but is still used to treat rheumatoid arthritis and other inflammatory diseases, so should be considered as a cause of LVH in patients treated with this drug.

We are all taught to make a differential diagnosis for every patient’s condition, but this is especially important with thick-hearted patients to avoid missing a treatable disease.

1. Maron BJ, Lesser JR, Schiller NB, Harris KM, Brown C, Rehm HL. Implications of hypertrophic cardiomyopathy transmitted by sperm donation. 

. 2009;302(15):1681-1684. doi: 10.1001/jama.2009.1507 [doi].

2. Ruberg FL, Grogan M, Hanna M, Kelly JW, Maurer MS. Transthyretin amyloid cardiomyopathy: JACC state-of-the-art review. 

. 2019;73(22):2872-2891. doi: S0735-1097(19)34729-1 [pii].

3. Maurer MS, Schwartz JH, Gundapaneni B, et al. Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy. 

. 2018;379(11):1007-1016. doi: 10.1056/NEJMoa1805689 [doi].

4. Germain DP, Hughes DA, Nicholls K, et al. Treatment of Fabry disease with the pharmacologic chaperone migalastat. 

. 2016;375(6):545-555. doi: 10.1056/NEJMoa1510198 [doi].

5. Yogasundaram H, Putko BN, Tien J, et al. Hydroxychloroquine-induced cardiomyopathy: Case report, pathophysiology, diagnosis, and treatment. 

. 2014;30(12):1706-1715. doi: 10.1016/j.cjca.2014.08.016 [doi].

Dr. Paul Thompson reflects on the diagnosis and treatment of hypertrophic cardiomyopathy and other comorbid conditions, in this column, titled "Don’t Be Thick Headed With Thick Hearts". 

Paul D. Thompson, MD: Don’t Be Thick Headed With Thick Hearts

I saw a patient years ago (August 2002) for triglycerides (TG) of 759 mg/dL despite pravastatin 20 mg daily. I started him on fenofibrate 145 mg daily, and he decreased his TGs to 300 mg/dL. The TGs got even better with high dose atorvastatin. He recently returned to see me prior to a lung transplant for advanced pulmonary fibrosis, but he had not yet been accepted for the transplant because his creatinine was 1.4 mg/dL. I stopped his fenofibrate and his creatinine decreased to 1.1 mg/dL 3 weeks later.

Many clinicians are unaware that fenofibrate can cause a reversible increase in creatinine because it interferes with creatinine excretion in the kidney. Creatinine values in the 5-year Fenofibrate Intervention and Event Lowering in Diabetes or FIELD study increased 12% soon after fenofibrate was started.

 A substudy of 661 FIELD participants demonstrated that creatinine increased when study drug was started in both groups, remained high in the fenofibrate group but fell promptly in the fenofibrate group when fenofibrate was stopped at the end of the 5-year study. The creatinine was actually lower in the fenofibrate group after the study demonstrating that fenofibrate improves renal function in diabetics. What a paradox…higher creatinine levels on the drug, but ultimately better renal function.

Fenofibrate is not the only lipid-lowering agent that raises creatinine. The new LDL cholesterol lowering drug, bempedoic acid, also increases creatinine by interfering with the organic anion transporter or OAT in the kidney. Bempedoic acid increases uric acid as well by a similar mechanism.

Please remember this increase in creatinine with fenofibrate and now with bempedoic acid. I have seen multiple patients over the years, who were told they were headed for dialysis, whose creatinine normalized after stopping the fenofibrate.

Some may ask why I use fenofibrate at all because the FDA now requires that the package insert for fenofibrate products state: “The effect of (fenofibrate) on coronary heart disease morbidity and mortality and non-cardiovascular mortality has not been established”.

 This is based primarily on the results of the Action to Control Cardiovascular Risk in Diabetes or ACCORD Trial.

ACCORD assigned statin-treated diabetics to either fenofibrate or placebo. There was no significant reduction in cardiovascular events with fenofibrate, but my gripe with ACCORD is that the subjects’ median baseline TG level was 162 with an interquartile mean of 113-229 mg/dl. I would not have treated many of these subjects with fenofibrate because their TGs were not high enough. If you look at the subgroup with TGs >203 and HDL-C’s <35 mg/dl, however, there was a reduction in events, but the 

-value was “not statistically significant” at 0.06, so not below the vaulted 0.05.

Concentrated fish oil is my first choice for treating TGs because the Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia or REDUCE-IT trial demonstrated a 4.8% absolute reduction in cardiovascular events with icosapent ethyl,

 but I still use fenofibrate for very high (fasting TGs >500 mg/dl) in combination with concentrated fish oil. Also, fenofibrate may have small vessel benefits, at least in diabetics. In FIELD, fenofibrate reduced amputations especially minor amputations, such as toes, and especially in individuals without large-vessel disease suggesting a small vessel benefit.

 (I would not consider losing my toes minor, but that’s their definition.) Similar to the reduced reduction in GFR noted above for FIELD, fenofibrate reduced both the need for first eye laser treatments and the progression of diabetic retinopathy in FIELD and ACCORD, respectively.

 Perhaps fenofibrate has a small (vessel) story to tell.

Dr. Paul D. Thompson tackles the topic of whether use of fenofibrate helps or harms kidney function. 

Paul D. Thompson, MD

Articles

Paul D. Thompson, MD: Is Digoxin Back from the Dead?

Compassion in Medicine: Give Them Back Their Clothes

Paul D. Thompson, MD: Don’t Be Thick Headed With Thick Hearts

Does Fenofibrate Help or Hurt Renal Function?