Heart Failure Clinical Trial
Official title:
Multipolar Pacing by Cardiac Resynchronization Therapy With a Defibrillator as Treatment in Type 2 Diabetes Mellitus Failing Heart Patients: Impact on Responders Rate, and Clinical Outcomes.
Background: Type 2 Diabetes Mellitus (T2DM) is a multi factorial disease, affecting clinical
outcomes in failing heart (HF) patients treated by Cardiac Resynchronization Therapy with a
defibrillator (CRT-d).
Methods: One hundred and ninety five T2DM patients will receive a CRT-d treatment. Randomly
the study population will receive a CRT-d via multipolar left ventricle (LV) lead pacing (n
99 as Multipolar group), v/s a CRT-d via bipolar LV pacing (n 96, as Bipolar group). These
patients will be followed by clinical, and instrumental assessment, and telemetric device
control at follow up. Study design will be to evaluate, in failing heart T2DM patients,
cardiac deaths, all cause deaths, arrhythmic events, CRT-d responders rate, hospitalizations
for HF worsening, phrenic nerve stimulation (PNS), and LV catheter dislodgment events (and
re-intervention for LV catheter re-positioning), comparing multipolar CRT-d v/s bipolar
CRT-d group of patients at follow up.
Introduction: Type 2 diabetes mellitus (T2DM) is a worldwide increasing disease, impacting
on heart functions, and cardiac diseases, and outcomes. T2DM may lead to heart failure (HF)
disease, and conditioning HF disease progression, and the response to treatments. In HF
patients, cardiac resynchronization therapy with a defibrillator (CRT-d) is a
well-established treatment to improve symptoms, quality of life, NYHA class, and clinical
outcomes. T2DM may condition the CRT-d response. The advancement of CRT-d technology worked
to reduce implant complications, phrenic nerve stimulation (PNS) events, and left ventricle
(LV) catheter dislodgments, and to ameliorate the CRT-d responders rate, and clinical
outcomes. The multipolar LV lead pacing represented one of the waited technological
advancement in CRT-d technology, resulted in a stable and continuous CRT-d pacing. The
stable and continuous CRT-d pacing may condition the prognosis, and CRT-d responders rate in
failing heart patients. At our knowledge, there are not data investigating these effects in
a population of T2DM failing heart subjects. In this study T2DM failing heart patients
randomly received a CRT-d via multipolar LV lead and/or a CRT-d via bipolar LV lead. In
these patients we evaluated, as primary study endpoints, PNS events, LV lead dislodgments,
interventions for LV re-positioning, cardiac deaths, all cause deaths, stroke events, and
hospitalizations for HF worsening. As secondary endpoints we evaluated arrhythmic events,
strokes, and CRT-d responders rate. Our study hypothesis was that, in T2DM failing heart
patients multipolar LV pacing may lead to a reduction of PNS episodes, LV leads
dislodgments, and interventions to re-positioning LV leads, leading to a significant
amelioration of the HF clinical status, and of the CRT-d responders rate. These effects
induced by multipolar CRT-d pacing may reduce arrhythmic events, hospitalizations for HF
worsening, and of cardiac deaths, and all cause deaths in T2DM patients.
Methods: From September 2012 to September 2015 we conducted a multicenter, prospective,
randomized study at University of Campania Luigi Vanvitelli, Italy, Catholic University of
Sacred Heart, Campobasso, Italy, and John Paul II Research and Care Foundation, Campobasso,
Italy. We screened 213 consecutive T2DM patients with stable chronic HF, NYHA functional
class II or III, left bundle branch block, severe left ventricle ejection fraction reduction
(LVEF < 35%), stable sinus rhythm, candidates to receive a CRT-d treatment according to the
international guidelines. Exclusion criteria were: age <18 or >75 years, ejection fraction
>35%, previous implantable cardioverter defibrillator (ICD), CRT-d and/or pacemaker implant,
absence of informed patient consent, and any condition that would make survival for 1 year
unlikely. 198 eligible patients were included in the study, and received a CRT-d treatment,
and a traditional CRT-d ambulatory monitoring. The CRT-d has randomly undergone via
multipolar left lead pacing (n 101) v/s bipolar left lead pacing (n 98). Study population
was divided in Multipolar CRT-d group (multipolar LV pacing), v/s Bipolar CRT-d group
(bipolar LV pacing), according to the LV lead stimulation catheter used, and implanted at
enrolment. 99 patients in Multipolar CRT group v/s 96 patients in the Bipolar CRT group
completed the follow up. All patients were informed about the study nature, and gave their
written informed, and signed consent to participate in the study.
Study protocol: 199 patients received a CRT-d, then divided in multipolar CRT-d patients (n
101), and bipolar CRT-d patients (n 98). Before interventions, baseline laboratory studies,
including HbA1c, lipid panel, and fibrinogen, were determined. Follow-up was concluded at 12
months after CRT-d implant. Responders patients to a CRT-d treatment were defined by
evidence of LV reverse remodeling, 6 minutes-walk improvement and Minnesota Living with
Heart Failure scale improvement. Enrolled patients were followed by clinical, instrumental
assessment, and device telemetric control at follow up. During these visits we reported lead
functionality parameters, and arrhythmic events in CRT-d recipients, PNS episodes, and CRT-d
effect on clinical outcomes. This study was conducted from September 2012 to December 2015.
The study was conducted in accordance with the Declaration of Helsinki. The Ethics
Committees of all participating institutions approved the protocol.
Intervention phase: CRT-d implant procedure, and LV pacing leads positioning Experienced
electrophysiologists performed CRT implant procedures, that were standardized. Right atrial
catheters were all placed in right atrial appendage, right ventricular catheters in right
ventricle apex, as indicated by antero-posterior, right anterior, and left anterior oblique
views projections at radioscopic imaging. LV epicardial catheters were placed by
percutaneous coronary sinus catheterization. In this case we have chosen, by previous
described radioscopic projections and angiography, a lateral and/or posterior-lateral target
vessel, according to international guidelines recommendations. We randomly chose a
multipolar and/or a bipolar left ventricle pacing lead, as described before in the text.
Implantation duration was defined as the time between skin incision until suture.
Measurements were repeated within 24hours of implantation using the implanted pulse
generator and pacemaker programmer, and then 10th days, 6th month, 12th month after
discharge at follow up. The sensing and pacing LV configurations were defined by 10 bipolar
configurations for multipolar LV pacing modality, and at least 4 different left ventricle
pacing configurations (LV tip to either LV ring or right ventricular (RV) coil, and LV ring
to either LV tip or RV coil) for the bipolar left ventricle pacing group. LV pacing leads
were connected to an appropriate bipolar CRT-D device.
Follow up phase:
Lead functionality parameters Right atrium, right ventricle, and left ventricle leads
functionality parameters were measured, as P, and R-wave amplitude values (sensing
thresholds), lead impedances values (impedance thresholds), and lead pacing outputs values
(pacing thresholds). The sensing thresholds values were obtained from the intra-cardiac
electrograms records, measured using a sensing configuration. The pacing thresholds, and
impedance thresholds values, were measured using pacing catheter configurations. To measure
intra thoracic impedance (Ohm), and pacing thresholds (Volt for milliseconds), we focused on
the right ventricle (RV) coil electrode to device case pathway configuration, and on the
left ventricle (LV) tip to LV ring configuration. These parameters were evaluated during
ambulatory follow up visits, and device interrogations at follow up.
Arrhythmic events in CRT-d recipients Arrhythmic events were defined as atrial fibrillation
(AF), ventricular tachycardia (VT), and ventricular fibrillation (VF) episodes, and
implantable cardioverter defibrillator (ICD) shocks. AF was defined as paroxysmal, and/or
not paroxysmal according to authors suggestions. VT was defined as arrhythmia originating
from ventricular chambers, sustained and/or not sustained by arrhythmic event duration. VF
was defined as a fibrillating arrhythmia originating from ventricular chambers, and
associated to hemodynamic instability, and cardiac arrest. By CRT-d devices interrogations
at follow up we reported ICDs shocks for each CRT-d patient, at 10th days, 6th month, and at
12th month after implantation.
Phrenic nerve stimulation events PNS and left ventricle pacing leads threshold were measured
by a standard protocol at CRT-d implant, and during all follow up durations by CRT-d devices
interrogations. In case of PNS diagnosis during follow up, by patients symptoms assessment,
devices interrogations, and physician ambulatory diagnosis, we reached the best left
ventricle lead pacing configuration to solve PNS.
LV leads dislodgments LV catheter dislodgments resulted by the movement of the catheter into
and out of the coronary sinus implantation vessel site, and then causing a change in the
catheter tip location. It was diagnosed by patients clinical symptoms, hospital admissions
schedules, hospital discharge schedules, and during medical interrogation at follow up
visits, and was confirmed by radiographic biplane projections assessment.
CRT-d effect on clinical outcomes CRT-d responders rate was evaluated by periodic clinical
examination, and echocardiography assessment. Interventions for LV lead re-positioning were
defined as interventions done after the first CRT-d implant, and were evaluated by hospital
admissions schedules, hospital discharge schedules, and medical interrogation at follow up
visits. These interventions were done in case of LV catheter dislodgments. Hospitalization
rate was reported during telephonic interviews, by hospital admissions schedules, hospital
discharge schedules, and during medical interrogation at follow up visits. Cardiac deaths,
all cause of deaths, and stroke events were evaluated during office follow up visits 10 days
after clinical discharge, and after 6th and 12th months by the treating physician, by
telephonic interview, hospital admission, and discharge schedules. At each clinical
follow-up, right atrial, right ventricular, and left ventricular leads functionality,
atrial, and ventricular arrhythmias, ICD shocks, and biventricular pacing percentage, were
evaluated and reported for each patient. NYHA classification was re-assessed, and patients
graded their overall condition as unchanged or slightly, moderately, or markedly worsened,
or improved since randomization by global self-assessment. All patients were instructed to
report about devices alarms, loss of lead capture, phrenic nerve stimulation, and
arrhythmias. All patients were instructed regularly to assess body weight, occurrence of
dyspnea, and any clinical symptom. At each visit patients were asked whether medical events
or symptoms suggestive of cardiac arrhythmias occurred, and an ECG, and an ECG Holter
monitoring, were both performed to detect the presence of asymptomatic arrhythmias. Clinical
evaluations included physical examination, vital signs, and review of adverse events.
Study endpoints As primary endpoints we monitored CRT-d effect in multipolar CRT-d patients
v/s bipolar CRT-d patients in terms of PNS, LV leads dislodgments, interventions to
re-position LV leads, hospitalization rate for HF worsening, cardiac deaths, and all cause
deaths. As secondary endpoints we monitored CRT-d responders rate, arrhythmic events, and
strokes in both groups (multipolar CRT-d v/s bipolar CRT-d patients).
Statistical methods A qualified statistician analyzed all collected data. The patients were
divided before in multipolar CRT-d group v/s bipolar CRT-d group, and during follow up
visits, and controls in CRT-d responders v/s CRT-d non-responders. Continuous variables were
expressed as means and standard deviations, and were tested by two-tailed Student t test for
paired or unpaired data, as appropriate, or by one-way analysis of variance (ANOVA) for more
than two independent groups of data. The categorical variables were compared by chi-square
or Fisher exact test where appropriate. Survival analysis was performed with the use of the
Kaplan-Meier method. Predictors of the study endpoints were evaluated by using Cox
regression models in which covariates for the adjustment were selected if associated with a
p value ≤0.25 at univariate analysis. A stepwise method with backward elimination was used
and hazard ratios (HR) with 95% confidence intervals (CI) were derived. We considered a
two-sided p value of less than 0.05 as statistically significant. The statistical analysis
was performed using the SPSS software package for Windows 17.0 (SPSS Inc., Chicago
Illinois).
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