Clin Res Cardiol (2021)
DOI DOI https://doi.org/10.1007/s00392-021-01843-w

Serum drug concentration and cardiotoxicity in patients with heart failure and depression treated with escitalopram: Insights from the MOOD-HF randomized clinical trial

L. Barthel1, S. Unterecker2, S. Lezius3, S. Störk1, K. Wegscheider3, G. Ertl4, J. Deckert2, C. E. Angermann1, für die Studiengruppe: MOOD-HF
1Deutsches Zentrum für Herzinsuffizienz, Universitätsklinikum Würzburg, Würzburg; 2Klinik und Poliklinik für Psychiatrie, Psychosomatik und Psychotherapie, Universitätsklinikum Würzburg, Würzburg; 3Zentrum für Experimentelle Medizin, Institut für Medizinische Biometrie und Epidemiologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg; 4Medizinische Klinik und Poliklinik I, Universitätsklinikum Würzburg, Würzburg;

Background In the MOOD-HF study 18-months treatment with escitalopram neither improved clinical outcomes in depressed patients with chronic systolic heart failure (HF) nor depressive symptoms, and exploratory analyses suggested unfavorable side effects. 

Aim This sub-study explored factors affecting escitalopram serum levels (ESL) and, whether effects escitalopram treatment on depression, cardiac biomarkers, and health status (Kansas City Cardiomyopathy Questionnaire [KCCQ]) depended on ESL.  

Methods Study medication was up-titrated to 20 (10) mg/day in patients <65 (≥65) years as tolerated, and guideline-directed medical HF therapy (GDMT) optimized. Dosages reached at 12 weeks were fixed as maintenance dose. Biosamples for later assessment of trough ESL were obtained at all study visits. Eligible patients were grouped according to study arm (controls [n=150] vs treatment [T, n=137]) and 12-weeks ESL (T1[subtherapeutic]: <20 ng/mL, n=29; T2[therapeutic]: 20-80 ng/mL, n=82; T3[supratherapeutic]: >80 ng/mL, n=26).

Results Overall, baseline characteristics did not differ between controls and T-patients. Across T1-T3 groups higher age, N-terminal pro-B-type natriuretic peptide (NT-proBNP) and troponin (hsTrop) levels and lower glomerular filtration rate were associated with higher ESL (p<0.001, p=0.035, p=0.002 and p=0.027, respectively). Average 12-month escitalopram doses were T1: 12.7±5.7mg, T2: 14.8±4.3mg, T3: 16.3±3.9, p<0.01. Irrespective of ESL, escitalopram did not improve depression in T-patients vs. controls. After 12 months of treatment, baseline NT-proBNP had decreased by 36% with optimized GDMT in controls+T1 (p<0.001), but was unchanged in T2+T3 (pgroups =0.028) (Figure A); mean QTcBazett was unchanged in controls+T1, but increased by 11.2 ms in T2+T3 (p=0.028). Whereas hsTrop and KCCQ Symptom Score had improved by 30% and 8.25 points in controls, respectively (p=0.001 and p<0.001), values tended to increase (hsTrop, see Figure B) or improve less (KCCQ) in T-groups resulting in significant group differences (pgroups=0.005 and =0.049, respectively).

Conclusion Higher dosage, but also older age, more severe HF and renal dysfunction were associated with higher ESL. Escitalopram lacked therapeutic efficacy in this HF population, irrespective of ESL. Even at therapeutic doses/ESL, adverse effects on cardiac biomarkers, QTc prolongation and inferior health status (KCCQ) suggest significant ESL-related cardiotoxicity.

Figure: Time course of changes in N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels (A) and high sensitivity Troponin T levels (Troponin) (B) during 12-months treatment with escitalopram (T) or placebo (Control) in patients with chronic systolic heart failure. T1-T3 denote patients with subtherapeutic, therapeutic and supratherapeutic escitalopram serum levels (ESL).

 
https://dgk.org/kongress_programme/jt2021/aP635.html