Study of Myocardial Recovery after Exercise Training in Heart Failure

This protocol describes a randomized multicenter clinical trial designed to
test the hypothesis that a 12-week program of aerobic interval training (AIT)
yields larger beneficial effects in stable heart failure patients than current
practice, defined as either a similar training program with the same volume of
moderate continuous training (MCT) or a recommendation of regular exercise at
moderate intensity at individual choice (RRE). Evaluation criteria are left
ventricular dimensions and function measured by echocardiography, aerobic
capacity measured as peak oxygen uptake, quality of life, and the level of
physical activity by questionnaires. Assessments will be made before and after
the training program and at one year follow-up. Safety of AIT will be assessed
as incidence of adverse effects during the training program. Clinical events
will be recorded as worsening of heart failure requiring intensified drug
therapy (diuretics), ventricular arrhythmia, hospitalization due to
cardiovascular disease, and all-cause mortality at one year follow-up.

The extent of beneficial effects of AIT, including reverse remodeling and
improved left ventricular function, exercise capacity, quality of life and
level of physical activity, needs to be established in a phase II type clinical
multicenter study with sufficient statistical power.
Safety of AIT during the supervised 12 week training program needs to be
assessed.
Maintenance of beneficial effects beyond the supervised training period needs
to be determined.
The incidence of clinical events like death, cardiovascular hospitalization,
ventricular arrhythmia, and worsening of heart failure requiring intensified
drug therapy (diuretics) needs to be estimated in order to indicate whether a
phase III type clinical trial is warranted, and potentially for study size
calculation.

The study will comprise all-cause heart failure patients, with coronary artery
disease and dilated cardiomyopathy as main etiologies. Recruitment will be from
outpatient heart failure management clinics and from patients referred to
cardiac rehabilitation. All patients with LVEF <0.35 and NYHA class II-III will
be assessed for eligibility and registered (see flow chart and Clinical
Research Form, CFR). There will be no age limit, as most HF patients are
elderly, but functional limitations of the ability to complete an exercise
training program will be taken into consideration.

AIT group * Patients will warm up for 10 minutes at moderate intensity
(corresponding to 50-60% of VO2peak, 60-70% of peak heart rate, 11-13 Borg
scale, no shortness of breath) before walking/cycling four 4-minute intervals
at high intensity (corresponding to 85-90% of VO2peak, 90-95% of peak heart
rate, 15-17 Borg scale, shortness of breath). Each interval will be separated
by 3-minutes active pauses, walking at 50-70% of peak heart rate. The training
session will be terminated by 3-minutes cool-down at moderate intensity. Total
exercise time will be 38 minutes for the AIT group. Special procedures for
adjusting training intensity in patients with atrial fibrillation and patients
carrying an ICD are described in the SOP.

MCT group * Patients will walk continuously at moderate intensity (as defined
above) for 47 minutes each session to assure the training protocols are
isocaloric (based upon previous studies21). All subjects will use a heart rate
monitor to obtain the assigned exercise intensity. The Borg 6-20 scale will be
used to measure the rate of perceived exertion during and after each training
session. The speed and inclination of the treadmill or the load on the bicycle
ergometer will continuously be adjusted, to ensure that every training session
will be carried out at the assigned heart rate throughout the 12-week training
period.

The RRE group * Patients will be advised to exercise regularly in activities
of their own preference. In addition they will meet for continuous treadmill
walking of individual duration at 50-70% of peak heart rate for 20-30 minutes
every three weeks, in order to motivate for post intervention testing. For
safety, patients in the AIT and MCT patients will be checked briefly for signs
of adverse effects by nurse or physician before training sessions every two
weeks; for practical reasons RRE patients will be checked every three weeks.

.

Cardio-pulmonary exercise testing
Echocardiography
Quality of life questionnaire (KCCQ, HADS, GMS, Type D)
Level of Physical Activity (IPAQ questionnaire)
Registry adverse events
Holter
ICD interrogatie
60 ml blood at begin of the study