Digoxin Evaluation in Chronic heart failure: Investigational Study In Outpatients in the Netherlands

Heart failure (HF) is common, disabling, and associated with an impaired
survival. Approximately 1-2% of the population in European countries is
diagnosed with HF, and in the Netherlands there are currently 150,000 patients
with HF, which may even be an underestimation of the true prevalence of HF.The
prevalence of HF is still increasing; currently the lifetime risk for
developing HF is one in five for both men and women. Although recent advances
in pharmacotherapy, patients diagnosed with HF have a poor quality of life and
a poor prognosis with a 5-year survival rate less than 50% which is even worse
than patients diagnosed with bowel or breast cancer. In addition, HF is also a
very costly disease accounting for ~2% of the total health care budget in The
Netherlands. Especially hospitalization for HF is extremely expensive yielding
60-70% of the total costs for HF. Therefore, reducing HF hospitalizations will
not only improve patient*s quality of life (QoL) and life expectancy but will
also lead to a significant reduction in health care related costs.

Atrial fibrillation (AF) is one of the most common comorbidities in patients
with HF with a prevalence of 25 to 40%. The combination of AF and HF is
associated with even a further increased risk of hospitalizations and
mortality. Despite its high prevalence in HF, patients with AF were
underrepresented in prior HF trials. So far, none of the rate or rhythm control
therapies have shown to improve the prognosis of patients with AF, and all are
only used to reduce symptoms.

Digoxin is the oldest drug for HF, and very cheap. A large trial with digoxin
revealed a highly significant reduction in HF hospitalizations, but no effect
on mortality. Due to these ambiguous findings and since subsequent large trials
with ACE-inhibitors, beta-blockers and later mineralocorticoid receptor
antagonists demonstrated improved survival, the clinical use of digoxin has
largely diminished in the last decade. In everyday clinical practice, digoxin
is nowadays used only in a minority (~10%) of the HF patients.

However, later analyses of the DIG study showed that (in hindsight) too high
doses were probably used in the DIG trial. Indeed patients with lower serum
concentrations of digoxin showed a better survival. While serum digoxin
concentrations between 0.5-0.9ng/mL were related to lower mortality, all-cause
hospitalization and HF hospitalization, digoxin concentrations >1.0ng/mL were
associated with a higher mortality.


In HF patients with AF, digoxin is recommended for rate control to reduce
symptoms, but not for prognosis. However, based on post-hoc analysis of several
AF databases, digoxin*s use is declining in the last decade due to concerns of
increased mortality risk.15,16 In these datasets the use of digoxin was mostly
restricted to sicker patients, leading to confounding by indication and
prescription bias, and again (too) high doses were used.

Therefore, a randomized placebo-controlled trial in patients with chronic HF,
with a wide range of left ventricular ejection fraction (LVEF) (reduced and
mid-range ejection fraction of respectively <40% and between 40 and 50%) is
necessary.

This study has been transitioned to CTIS with ID 2023-509898-23-00 check the CTIS register for the current data.

To study whether low-level digoxin reduces the composite primary endpoint of
(repeated) HF hospitalizations, (repeated) urgent HF hospital visits and
cardiovascular mortality, compared to placebo, in chronic HF.

The proposed trial is a national, multicenter, randomized, double-blind placebo
controlled, clinical trial

Patients will be randomized to low-level digoxin or placebo in double-blinded
fashion. Digoxin will be given orally starting at doses of 0.2mg, or 0.1mg,
based on age, renal function and concomitant medication. No loading dose is
given. After 4 weeks study medication (digoxin or placebo) concentrations will
be measured. Dose adjustments will be made to reach the target serum digoxin
concentration range of 0.5-0.9ng/mL.

In DECISION, we use low-level digoxin and aim for low serum concentrations
(0.5-0.9ng/mL). We will measure serum digoxin concentrations throughout the
duration of the trial, to make the chance of overdosing as low as possible.
Therefore, we expect side effects or intolerance for digoxin only in a minority
of patients. Mostly, digoxin intoxications occur with concentrations >2ng/mL.
The most common side effects of digoxin are dizziness, visual disturbances,
arrhythmias, nausea, vomiting, diarrhea, and exanthema. For study purpose,
patients are seen at outpatient clinic at inclusion, 1-month, and then every 6
months, and between the outpatient visits telephone checks are planned, a
minimum of 7 outpatient visits (= routine clinical practice for HF patients),
and 6 telephone checks. Blood samples for measurements of serum digoxin
concentration will be performed at least 7 times, and 1-month after all study
medication dose adjustments, when interacting medication is started, when renal
function decreases (eGFR <45 ml/min/1.73m2), after a hospitalization for HF,
and every 6 months during study follow-up. Patients are asked to fill in
quality of life and medical consumption questionnaires.