Background:
Heart failure (HF) is a disease that affects more than 60000 patients in Denmark and
millions across the world. The prognosis of HF is comparable to many types of cancer. New
onset HF is observed in up to 25% of patients with incident atrial fibrillation or
flutter (AF). The persistent tachycardia caused by AF is believed to exert the heart to a
point where it causes HF. Whether AF is the cause of HF, or conversely that the
detrimental effects of HF has induced AF, is difficult to ascertain upon the initial
presentation. Current guidelines suggest that both conditions (AF & HF) be addressed with
guideline directed medical therapy (GDMT) for HF and rate or rhythm control of AF. GDMT
for HF consists of at least 4 different types of medication which is combined with
management for AF (anticoagulant and often antiarrhythmic medication or ablation
procedures). Hence, patients with both conditions are subjected to polypharmacy with at
least 6 different types of medication in addition to their usual medication regimen. This
may have prognostic benefits, but also possible side effects, such as decreased renal
function, dizziness, tiredness and hypotension, as well as the financial burden on both
the individual patients and society, in addition to the stigma of having a heart failure
diagnosis.
Gaps in knowledge Data are lacking on how to optimally manage patients long-term with
heart failure suspected to be tachycardia-induced, who following cessation or control of
the incident AF, show full recovery from their heart failure condition. Guidelines do not
suggest whether GDMT for heart failure should continue lifelong, cease or be weaned. In
the TRED-HF study, 51 non-ischemic HF patients with LVEF recovery who were seemingly
clinically stable were weaned from GDMT. Approximately 40% of patients showed signs of
deterioration after 6 months of incremental GDMT weaning. Where TRED-HF patients had
verified longstanding chronic HF, the situation for patients experiencing an incident
episode of AF subsequently leading to acute heart failure may represent a different
phenotype with a better prognosis once AF is terminated or controlled as suggested by
observational data. Currently there is no data supporting how to manage GDMT in this
population of heart failure patients with recovery following control of their AF episode.
Objective:
To observe whether incremental weaning of GDMT in patients following full cardiac
recovery and AF control is non-inferior compared to continuous GDMT.
Furthermore, using an extensive phenotypic profiling, to investigate if one or more
biomarkers can predict which patients are at an increased risk of cardiac deterioration
in both intervention groups.
Hypothesis:
The investigators hypothesize that patients weaned from GDMT will experience similar
rates of deterioration as patients on continuous GDMT.
Perspective The chance of remission after a heart failure diagnosis differs greatly
depending on the etiology of heart failure. Although dramatic differences in remission
rates depending on etiology have been established, patients with heart failure are in
general committed to the same regimen of GDMT. For example, in patients with
alcohol-induced heart failure, removing the cardiotoxic substance (alcohol) through
abstinence leads to recovery in >50% of cases. Genetic profiling reveals that changes in
mutations leading to alterations in cardiac structural proteins - titin - are very
prevalent in patients with alcohol-induced heart failure. It appears that patients may be
at increased risk of heart failure if they both have a genetic disposition combined with
a cardiotoxic stimulus (e.g. alcohol, tachycardia). Interestingly, mutations in the same
titin gene has also been found in many patients with atrial fibrillation. Therefore, it
is plausible that if the detrimental effects of prolonged tachycardia could be stopped a
continuous HF remission in our cohort would be observed. This study seeks to extensively
phenotype patients with tachycardia-induced heart failure in order to establish whether
certain phenotypes are at lesser or greater risk of deterioration once remission is
established. This novel approach of a personalized heart failure treatment regimen
depending on genetic profiling and advanced imaging could lead to an aggressive treatment
in patients at high risk of deterioration and conversely spare patients with a negligible
risk of deterioration a life-long intensive treatment regimen.
Primary endpoint:
Patients free from heart failure deterioration 1 year after randomization
Secondary endpoints 1 year after randomization:
Changes in Minnesota Living with Heart Failure Questionnaire from baseline (min.
score 0 - max. score 105, where higher scores indicates worse quality of life)
Hospitalization for heart failure
Cardiovascular (CV) hospitalizations
Non-CV hospitalizations
CV death
All-cause death
Patients in need of initiation of loop diuretics or doubling of dosage
Changes in N-terminal pro-Brain Natriuretic Peptide (NT-proBNP) from baseline
Patients needing changes in medication for AF (uptitration of current medication or
change in/addition of new medication) or re-do ablation for AF
Patients with signs of AF that persistently exceed 110 bpm despite best practice
Adverse events will be summarized;
Patients with renal deterioration, hypotension, dizziness.
Patients with signs of new onset liver affection and/or thyroid dysfunction
Methods:
This is an investigator-initiated, open-label, randomized, non-inferiority trial. This
clinical trial complies with the Declaration of Helsinki, modified in 2013. This study
has been approved by both the ethical committee (H-23010220) and the Knowledge Centre on
Data Protection Compliance in the Capital Region of Denmark (P-2023-111). This trial will
adhere to good clinical practice guidelines (GCP).
Patients with HF who are followed in HF clinics on Zealand including the greater
Copenhagen region are screened. This area covers >2 million citizens (approximately 1/3
of all citizens in Denmark). All patients fulfilling criteria for participation will be
invited to participate. HF specialists at each HF clinic will assess eligibility based on
a review of the medical chart and an individual assessment. Patients can be rescreened
for inclusion repeatedly throughout the inclusion period.
Collaborators:
This trial is executed, analyzed and published by the main applicant and nested at
Herlev-Gentofte Hospital. A collaboration between the applicant and heart failure clinics
is pivotal in order to ensure timely inclusion of a generalizable heart failure
population and to swiftly implement the findings into clinical practice.