Multipolar CRT-d and Diabetes
Condition: Diabetes; Heart Failure; Heart Failure NYHA Class II; Heart Failure NYHA Class III
MeSH terms: Heart Failure; Diabetes Mellitus
Study type: Observational

Summary: 
      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.
    

Detailed description: 
      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).
    

Intervention name(s): Multipolar CRT-d, plus conventional drug therapy for HF.; Bipolar CRT-d, plus conventional drug therapy for HF.; HF drugs
Intervention type(s): Device; Device; Drug
Intervention description(s): A random CRT-d implant performed via multipolar left ventricle lead, in failing heart patients treated by maximal drug therapy.; A random CRT-d implant performed via bipolar left ventricle lead (group B), in failing heart patients treated by maximal drug therapy.; full medical therapy to treat HF symptoms and its progression.
Observational model: Cohort
Time perspective: Retrospective
Sampling method: Probability Sample
Study population: 
        213 consecutive T2DM patients with stable chronic heart failure, New York Heart Association
        (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 as follows:
        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.