Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT01652248 |
| Other study ID # |
08/H1307/47 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
July 23, 2012 |
| Last updated |
December 1, 2015 |
| Start date |
April 2008 |
| Est. completion date |
May 2012 |
Study information
| Verified date |
December 2015 |
| Source |
University of Leeds |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
United Kingdom: National Health Service |
| Study type |
Interventional
|
Clinical Trial Summary
Patients with pacemakers often have undiagnosed heart muscle weakness. When a pacemaker
battery has run down, it is easily replaced by a short procedure. In those with heart muscle
weakness, who use their pacemaker most of the time (rather than acting just as a back-up)
the investigators want to find out if adding a further lead to their pacemaker system
improves their heart's function, kidney function and exercise capacity.
Description:
Background
1. Chronic heart failure Chronic heart failure (CHF) is a common syndrome of
breathlessness and fatigue associated with left ventricular systolic dysfunction. It
affects 2% of individuals between 50 and 60 years of age, and increases in prevalence
to 10% over the age of 80 years.
2. Cardiac resynchronisation therapy Cardiac resynchronisation therapy (CRT) involves the
implantation of a pacemaker capable of stimulating the heart (specifically the left
ventricle) from both the front of the heart, the right ventricle RV (as is usual with
conventional pacemakers) and from the back of the heart (known as the lateral wall) via
the coronary sinus, aiming to improve the timing of cardiac contraction (dyssynchrony)
and hence the pumping function of the heart in order to improve symptoms of
breathlessness and fatigue.
Early data in patients with left bundle branch block and severe heart failure,
suggested improved exercise capacity and left ventricular function. More recent data
have demonstrated not only improved symptoms, but also reduced hospital admissions, and
improved overall mortality.
Current guidelines drawn up using the data from randomised trials, suggest that CRT
should be offered to patients with left bundle branch block with a QRS > 150ms and
severe (class III and IV) heart failure despite optimal medical therapy. Patients with
a QRS duration of between 120 and 150ms should be assessed for mechanical dyssynchrony
before being offered a device.
3. Heart failure in the pacemaker population
- Prevalence In 307 patients with pacemakers, 94 (31%) had left ventricular ejection
fraction (LVEF) < 40% and 83 (27%) had symptoms of heart failure. RV pacing is
associated with an increase in heart failure-related hospitalisation and
mortality, and in patients with left ventricular dysfunction the presence of a
right ventricular apical pacemaker is a strong predictor of future deterioration
in left ventricular function.
- Aetiology of pacemaker-related heart failure Many patients receiving RV pacemakers
are elderly with a background of ischaemic heart disease or hypertension, both of
which contribute to the development of heart failure. In addition RV pacing
induces dyssynchrony, no different to that of left bundle branch block (LBBB).
Dyssynchrony leads to altered regional blood flow and wall stress. The severity of
these perfusion abnormalities, the regional wall motion abnormalities and the
associated deterioration in global left ventricular function are directly related
to the duration of pacing. These changes can be identified after only 18 months of
pacing. The induction of dyssynchrony by RV apical pacing seems therefore to lead
to adverse LV remodeling, LV dilatation, asymmetrical hypertrophy.
- Management of pacemaker-related heart failure In any one patient the exact
aetiology of a deterioration of LV dysfunction is often unclear. What has become
routine practice however, is an attempt to avoid RV pacing unless absolutely
necessary and several programmes within commercially available devices now exist
to facilitate this. The options in patients with a high degree of heart block on
the other hand remain limited to aggressive medical therapy with beta-blockers and
angiotensin converting enzyme inhibitors.
The effects of upgrading conventional pacemaker systems to those capable of delivering
resynchronisation therapy have been incompletely investigated. There have only been
retrospective series examining the impact of upgrading conventional pacemakers to CRT
systems. Early data demonstrated the safety of adapting standard pacemakers to provide
biventricular stimulation and suggested improvements in LV function. One study,
involving 20 patients with chronic atrial fibrillation and AV nodal ablation, showed
that adding an LV lead was associated with improved LV systolic function, reduced
hospitalisations and improved quality of life. Other reports examining the impact of
CRT in patients with chronic RV pacing on acute echocardiographic variables of LV
systolic function and reductions in electromechanical delay and beneficial haemodynamic
effects of biventricular pacing in 15 and 20 patients with pre-existing RV pacemakers.
More recently a cross-over study of 44 patients requiring generator replacement
demonstrated improved symptoms and LV function with 3 months of CRT when compared with
3 months of RV pacing. There are also data from small series demonstrating improvements
of echocardiographic strain variables (in 12 patients) and symptoms in patients with
significant CHF upgraded from conventional pacemakers to CRT systems
4. Aim of this study We propose to randomise 50 patients with ventricular dysfunction
listed for pulse generator replacement to receive either a standard right ventricular
generator replacement, or to be upgraded to a resynchronisation device. These patients
will then be reassessed at six months to establish the effects of this policy on left
ventricular function and exercise capacity.
Experimental design
1. Patients All patients will have undergone an echocardiogram, exercise test and renal
function check as part of the survey of all patients undergoing pacemaker battery
change at Leeds General Infirmary. If reducing or avoiding RV pacing to below 80% is
not possible, patients with LV dysfunction (LVEF < 50%) will be invited to participate
in the randomised controlled trial of standard generator replacement or upgrade to CRT.
2. Procedures Patients will then be randomised to receive either an upgraded system or a
pacemaker generator replacement as standard. Following the implant, subjects will be
seen at 6 weeks and three months in the pacemaker clinic as is usual. The 6 monthly
visit will include repeat echocardiography, an exercise test with metabolic gas
exchange, repeat blood tests, 24 hour urine collection and symptom assessment.
- Devices Patients will either receive a standard pacemaker appropriate to their
pacing indication, but with the capacity of keeping RV pacing to a minimum if
possible, or will be implanted with an LV lead and a generator capable of
providing resynchronisation pacing.
- Risk of the implant procedure From large registries, left ventricular lead
implantation is successful in 92% and the procedure is safe with fewer than 8%
requiring re-operation and around 10% complication rate. In our experience of >
100 upgrades for severe symptomatic heart failure, we have had no deaths, one
re-operation for an initial failure to place the LV lead, and no infections.
- Patients with atrial fibrillation The presence of atrial fibrillation reduces the
benefit from CRT in randomised controlled trials. However, registries continue to
demonstrate similar overall benefits on symptoms and left ventricular function and
hospitalisation for both groups, albeit with no improvement in the rate of
maintenance of sinus rhythm following CRT. Recent data have suggested that
patients with AV node ablation and atrial fibrillation, have a similar symptomatic
response rate as patients in sinus rhythm whereas those without AV node ablation
do not benefit. It is therefore postulated that the benefits of CRT are dependant
upon a high percentage of resynchronisation pacing (> 90%) and that patients with
atrial fibrillation with an intact AV node fail to respond because of intermittent
intrinsic conduction. In the present investigation however, our patients will be
have demonstrated dependency upon ventricular pacing for rate support. We will
therefore include patients with atrial fibrillation in our study, albeit with a
stratified randomisation to ensure they are equally distributed between the
upgrade and standard generator change arm.
3. Endpoints The primary endpoint will be an improvement in left ventricular function as
measured by left by echocardiography. Secondary endpoints will include changes in
exercise capacity, renal function and quality of life score.
4. Power calculations
- Left ventricular function Previous short term studies provide some guide as to the
potential benefit of upgrading RV pacing systems to CRT. In patients with
important heart failure a population of 20 patients crossed over at three months
demonstrated an improvement in exercise capacity of 1.5ml.kg.min-1 from 12.5
(2.9)ml.kg.min-1 to 14 (3.0)ml.kg.min-1. There was also an improvement in LVEF
from 26.1(8)% to 34.8(9)% and a reduction in BNP from 2405pmol.l-1 (not normally
distributed) to 1667pmol.l-1. Each of these changes was significant to less than
the 0.02 level.
- Exercise capacity Although patients randomised into the present proposal will have
better baseline exercise capacity and less severe ventricular dysfunction than
patients recruited to previous studies of CRT, we will avoid the potential
disadvantage of cross-over, and will follow them up for longer. We therefore
expect similar magnitudes of benefit (5% improvement in LV function and 1.5
ml.kg.min¬-1). We estimate an LV lead implant failure rate of around 8%, and a
loss to follow up of 5%. Hence we estimate that to identify a significant
difference with a power of 90% between RV pacing and CRT after six months that we
need to recruit 50 patients (25 to each arm). Results will be analysed on an
intention to treat basis.
