Beta-blockers, depression, and anxiety after myocardial infarction: the BETAMI-DANBLOCK trial

Symptoms of depression and anxiety are common among patients with myocardial infarction (MI) and associated with reduced health-related quality of life and increased risk of recurrent major adverse cardiovascular events.1,2 The underlying causes of post-MI depression and anxiety are still a matter of elucidation.3 They may be pre-existing conditions caused by environmental, biological or genetic factors, as well as a response to the MI event itself and/or side effects of the treatments initiated.3 Beta-blocker therapy has been a cornerstone in secondary prevention following MI, based on trials conducted several decades ago documenting their beneficial effects on morbidity and mortality. Current guidelines for the management of patients with acute coronary syndrome support the use of beta-blockers for all post-MI patients.4,5 However, major advancements in the acute and long-term MI treatment with coronary revascularization and antithrombotic, lipid-lowering, and blood pressure-lowering drugs have prompted a re-evaluation of the role of beta-blockers in modern clinical practice.6 Recently, the REDUCE-AMI7 and REBOOT8 trials on MI patients without heart failure found no effect of beta-blocker therapy on their primary composite endpoints. In contrast, the BETAMI-DANBLOCK9 and ABYSS10 trials, also in patients without heart failure, found a beneficial effect of beta-blocker therapy on a primary composite endpoint of all-cause mortality and major adverse cardiovascular events. For a full assessment of the benefits and risks of beta-blockers, it is also necessary to consider the possible side effects. Beta-blocker therapy has been associated with neuropsychological side effects, including depression, anxiety, fatigue, and insomnia.11–15 The aim of this study was to investigate the effect of beta-blocker therapy on symptoms of depression and anxiety in post-MI-patients in the BETAMI-DANBLOCK trial.16 This was a prespecified sub-study of the joint BETAMI-DANBLOCK trial. BETAMI and DANBLOCK were multicentre, open-label randomized controlled trials conducted at 19 sites in Norway and 25 sites in Denmark designed to evaluate the effects of beta-blocker therapy after MI in patients with mildly reduced or preserved left ventricular ejection fraction (LVEF).16 The trials had almost identical designs and criteria for inclusion and exclusion. The protocols were harmonized from the time of trial design in order to allow us to conduct joint analyses based on pooled data. Further details on the design of the trials are described in previous publications.9,16 The trials were conducted in accordance with ICH-GCP Guidelines, approved by the relevant ethics committees and registered at ClinicalTrials.gov (identifiers NCT03778554, NCT03646357). Patients who provided written informed consent within 14 days after an MI with mildly reduced or preserved LVEF (≥40%) were eligible for participation. Exclusion criteria were medical conditions requiring or contraindicating beta-blocker therapy, e.g. clinical signs of heart failure. The trial design and additional inclusion and exclusion criteria have been described in detail previously.9,16 Clinical data, registry data, and patient-reported outcome measures (PROMs) including the Hospital Anxiety and Depression Scale (HADS) and the Patient Health Questionnaire-2 (PHQ-2) (BETAMI cohort only) were collected before randomization and throughout the follow-up period. All patients included were invited to complete PROMs and a self-reported screening question concerning adherence to their allocated treatment (described in the Appendix), either electronically or on paper, at 1-, 6-, 12-, and 18-months follow-up in BETAMI and at 3-, 12-, and 24-months follow-up in DANBLOCK. Patients who did not complete any PROMs during the trial period were excluded from this sub-study. Participants were randomized 1:1 stratified on trial sites (BETAMI) and LVEF (DANBLOCK), to receive usual care including a beta-blocker, or usual care without a beta-blocker. Dose and type of beta-blocker were at the discretion of the treating physician, but physicians were encouraged to give the highest tolerated dose. Patients randomized to no beta-blocker therapy while on beta-blockers at the index date had their beta-blockers discontinued by the treating physician as soon as clinically possible. The main outcome of this sub-study was the between-group difference in changes in depression (HADS-D) score from baseline to 12-month follow-up. Secondary outcomes were between-group difference in changes in anxiety scores (HADS-A), depression scores assessed by PHQ-2, and cases of depression and anxiety. HADS is a validated questionnaire for assessing symptoms of depression and anxiety.17 It comprises 14 items, with seven assessing depressive symptoms (HADS-D) and seven assessing anxiety symptoms (HADS-A), each rated on a 4-point Likert scale.18 Summarizing the responses within each subscale yields separate scores for depression and anxiety, each ranging from 0 to 21.18 Based on prior studies in patients with cardiovascular disease, a minimal clinically important difference of 1.7 points was used to interpret between-group differences in HADS-D and HADS-A.19 HADS-D or HADS-A scores of eight or more are considered indicative of clinically significant symptoms of depression or anxiety.17 Symptoms of depression were also measured with PHQ-2 in the BETAMI-cohort. The questionnaire consists of two questions about the level of depressed mood and anhedonia over the past two weeks.20 The maximum score is six, with a score of three or more considered an indicator of potential clinical depression.21,22 The number of patients included in BETAMI-DANBLOCK was determined based on power calculation for the primary composite endpoint of all-cause death or major adverse cardiovascular events.9,16 Time of completed PROMs is stated as number of months since baseline. Due to different follow-up intervals in BETAMI and DANBLOCK, time points are in the joint analyses classified in the following categories: baseline, 1–6 months from baseline, 12 months from baseline, and 18–24 months from baseline. For patients who completed several PROMs within a time window (i.e. both at 1 and 6 months in the BETAMI-cohort), the mean PROM-score in the time window was applied. The original time points are applied for analyses conducted by country. Analyses were prespecified and performed on the intention-to-treat population. The sub-group of doses ≥100 mg/day was added post hoc. Linear mixed models were applied to evaluate the between-group differences in changes in scores from baseline to each time point: 1–6 months, 12 months, and 18–24 months. The dependent variables were the HADS-D score, HADS-A score, and PHQ-2 score. The linear mixed models included fixed effects for treatment (beta-blocker vs no beta-blocker), time point (baseline, 1–6 months, 12 months, and 18–24 months), treatment × time interaction, and the factors used to stratify the randomization (LVEF over 50% and trial sites). The interaction term between treatment and time was included to estimate between-group differences [with 95% confidence intervals (CI)] in change over time. Additionally, patient-level random effects were included to account for individual variability within the trial population. The effect of beta-blockers on clinically significant symptoms of depression and anxiety was estimated as odds ratios (OR) in multivariable logistic regressions. The dependent variables were dichotomous variables for clinically significant symptoms of depression or anxiety (HADS-D or HADS-A scores ≥8), and the effect of beta-blocker therapy over time was identified by an interaction term between beta-blocker group and follow-up point. All analyses were adjusted for the stratification variables LVEF and trial site. A sensitivity analysis was conducted in which patients were categorized into either the beta-blocker group or no beta-blocker group based on self-reported adherence at each follow-up. Subgroup analyses were performed to examine the outcomes stratified by baseline characteristics, including HADS-D and HADS-A scores (