DosemeLOL - Exploring differences in metoprolol concentrations between sexes, a pilot study

Metoprolol is a commonly used beta-blocker, that is used for many indications
including hypertension, prevention of atrial fibrillation (AF), angina
pectoris, cardiac failure and migraine.
In women treated with metoprolol, a stronger effect on heart rate and blood
pressure, more side effects and higher blood concentrations have been reported
compared to men. While guidelines of the European Society of Cardiology state
that the dosage of cardiovascular drugs should be adjusted in women, there is
however, to date, no guidance on how to adjust the dose of metoprolol at start
or during treatment.

After cardiac surgery, a standard dose of metoprolol, 25 mg twice a day, is
given to all patients for the prevention of atrial fibrillation for a duration
of three months. To date there is insufficient knowledge on the
pharmacokinetics (PK), effects and side effects of this dose between men and
women. Similarly, in patients with an acute coronary syndrome (ACS), a standard
dose of metoprolol is started on indication in men and women. Therefore, the
aim of this study is to gain insight in the effect of sex on the PK, the
effects and side effects of metoprolol in a 2-population study, i.e. 1. when
given a standard dose after coronary artery bypass surgery (CABG) with heart
valve surgery for three months and 2. after acute coronary syndrome (ACS, i.e.
STEMI or NSTEMI).

The main (primary) objective is to study the influence of sex on the
pharmacokinetics (PK) of metoprolol in patients after CABG with heart valve
surgery and patients with a STEMI/NSTEMI who are prescribed a standard dosage
of metoprolol as part of standard of care. The secondary objective is to
determine the influence of sex on the effects and side effects of metoprolol
including need for dose adjustment or interruption. In these analyses, besides
the influence of sex, other patient characteristics like age, indication and
CYP2D6 genotype are explored.

The study is a low intervention clinical trial.
While patients undergoing a CABG with heart valve surgery will have a central
venous catheter (CVC) and arterial line as part of standard of care,
STEMI/NSTEMI patients will receive an extra venous catheter for blood sampling
for the purpose of the study. On the day of the PK evaluation, i.e. day three
after CABG surgery or any day after STEMI/NSTEMI, patients will be asked to
fasten from two hours prior to the morning dose of metoprolol until four hours
after this dose. The first blood sample will be taken right before the dose of
metoprolol in the morning and around 12 hours after the evening dose (trough
sample). For standardization, metoprolol will be taken with 50 ml of water
after which the patient is asked to remain in upright position for 30 minutes.
Over 12 hours, twelve blood samples (3ml) will be taken to determine the
concentration of metoprolol. At all sample moments, heart rate, heart rhythm
and blood pressure will be recorded. On the same day a blood sample will be
taken to determine CYP2D6 genotype. For both groups, at discharge, at the
routine visits around 2-3 weeks and 6-8 weeks after discharge, the metoprolol
dose (changes) or need for treatment interruption are monitored together with
effects and side effects of metoprolol.

All patients receive standard treatment and medication after either CABG with
valve surgery or STEMI/NSTEMI, including start of treatment with a standard
dose of twice a day 25 mg metoprolol tartrate and measuring blood pressure and
heart rate regularly at ICU or ward. In the CABG with valve surgery group the
already placed arterial line will be used to collect blood samples. In patients
in the STEMI/NSTEMI group, a venous catheter will be placed to collect blood
samples. Thirteen blood samples are taken during the PK evaluation part of this
study during hospital stay, this amounts to 39 mL in total. In addition,
patients are asked to fast from two hours prior to the morning dose of
metoprolol at 6:00 am until four hours after this dose, which will delay
breakfast with 2 hours. All other data collection is part of standard of care.
Follow up after 2-3 weeks is also part of standard care, therefore no extra
hospital visits are necessary. Patients will not receive any personal benefits
from this trial. The results of this study may be used to improve treatment
with metoprolol for future patients after CABG with valve surgery or
STEMI/NSTEMI, with special attention to possible dose differences based on sex
(and/or other covariates), therapeutic drug levels differences and reduction
of side effects, successively.