Efficacy of Implantable Cardioverter Defibrillator in Patients With Non-ischemic Systolic Heart Failure on Mortality

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Brief Title

Efficacy of Implantable Cardioverter Defibrillator in Patients With Non-ischemic Systolic Heart Failure on Mortality

Official Title

A DANish Randomized, Controlled, Multicenter Study to Assess the Efficacy of Implantable Cardioverter Defibrillator in Patients With Non-ischemic Systolic Heart Failure on Mortality. The DANISH Study

Brief Summary

      Primary objective: The primary objective of this study is to determine the efficacy of ICD
      therapy compared with control on the endpoint of death from any cause.

      Secondary objective: The secondary objectives of the study are to determine if ICD therapy
      reduces sudden death.

      Study design: Randomized, unblinded, controlled, parallel two group trial.

      Primary endpoint: Time to death from any cause.

      Sample size: In total, 1000 patients with 500 receiving ICD and 500 patients constituting the
      control group.

      Summary of Subject Eligibility Criteria: Patients with clinical heart failure, left
      ventricular ejection fraction (LVEF) ≤ 35%, non-ischemic etiology and NT-proBNP above 200
      pg/ml. Patients in NYHA class IV will only be randomised if also fulfilling criteria for a
      biventricular pacemaker.

      Control group: Patients receiving standard therapy for heart failure including
      ACE-inhibitor/Angiotensin-Receptor-Blocker and Betablocker unless not tolerated. Aldosterone
      antagonism is optional.

      Study Duration: The study comprises a screening period of up to 2 years, followed by a
      treatment phase of a minimum of 36 months.

      Randomisation: After fulfilling all eligibility criteria, subjects will be randomized 1:1 to
      receive ICD implantation or continue usual control. Randomisation will be stratified
      according to treatment with a biventricular pacemaker.

      Treatment: After randomisation patients allocated to ICD treatment should receive this as
      fast as possible and preferably within 2 weeks (latest 4 weeks). The ICD will be programmed
      with anti-tachycardia pacing and shock therapy.

      Assessments: Deaths and hospitalisations for heart failure, stroke or arrhythmias will be
      recorded throughout the study duration.

      Statistical Considerations: Median lifetime in the control group is expected to be 5 years. A
      p-value of 5% (2-sided) is required for significance together with a power of at least 80%.
      With a relative risk reduction of 25% a sample size of 812 patients in total is required. In
      order to allow for cross-over a sample size of 1000 is planned.

      Primary Endpoint Analysis: The principal analysis for the primary endpoint (time to death
      from any cause) will employ the intent-to-treat principle and use a survival analysis.

      Secondary Endpoint Analysis: All time-to-event secondary endpoints will be analyzed similarly
      to the primary endpoint.
    

Detailed Description

      Title: A DANish randomized, controlled, multicenter study to assess the efficacy of
      Implantable cardioverter defibrillator in patients with non-ischemic Systolic Heart failure
      on mortality.

      Indication: Prevention of mortality in patients at risk of sudden death.

      Primary objective: The primary objective of this study is to determine the efficacy of ICD
      therapy compared with control on the endpoint of death from any cause.

      Secondary objective: The secondary objectives of the study are to determine if ICD therapy
      reduces cardiovascular death as well as sudden death.

      Study design: Randomized, unblinded, controlled, parallel two group trial.

      Primary endpoint: Time to death from any cause.

      Sample size: In total, 1000 patients with 500 receiving ICD and 500 patients constituting the
      control group.

      Summary of Subject Eligibility Criteria: Patients with clinical heart failure, left
      ventricular ejection fraction (LVEF) ≤ 35%, non-ischemic etiology and NT-proBNP above 200
      pg/ml. Patients in NYHA class IV will only be randomised if also fulfilling criteria for a
      biventricular pacemaker.

      Control group: Patients receiving standard therapy for heart failure including
      ACE-inhibitor/Angiotensin-Receptor-Blocker and Betablocker unless not tolerated. Aldosterone
      antagonism is optional.

      Study Duration: The study comprises a screening period of up to 2 years, followed by a
      treatment phase of a minimum of 36 months.

      Screening and Randomisation: After the signing of informed consent, screening will include
      medical history, vital signs, physical exam, blood chemistry, haematology, and NT-proBNP.
      After fulfilling all eligibility criteria, subjects will be randomized 1:1 to receive ICD
      implantation or continue usual control. Randomisation will be stratified according to
      treatment with a biventricular pacemaker.

      Treatment: After randomisation patients allocated to ICD treatment should receive this as
      fast as possible and preferably within 2 weeks (latest 4 weeks). The ICD will be programmed
      with anti-tachycardia pacing and shock therapy.

      Assessments: Deaths and hospitalisations for heart failure, stroke or arrhythmias will be
      recorded throughout the study duration. An Endpoint Classification Committee will adjudicate
      hospitalizations and deaths for causality.

      An independent Data Monitoring Committee will periodically review mortality data throughout
      the study.

      Statistical Considerations: Median lifetime in the control group is expected to be 5 years. A
      p-value of 5% (2-sided) is required for significance together with a power of at least 80%.
      With a relative risk reduction of 25% a sample size of 812 patients in total is required. In
      order to allow for cross-over a sample size of 1000 is planned.

      As event rate was lower than expected the steering committee decided to prolong follow-up and
      increase sample size slightly to 1150 patients. Secondly, the steering comittee decided to
      add cardiovascular death as a secondary outcome.

      Primary Endpoint Analysis: The principal analysis for the primary endpoint (time to death
      from any cause) will employ the intent-to-treat principle and use a survival analysis. For
      each treatment group, Kaplan-Meier curves will be estimated, graphically displayed, and
      compared using a logrank test. A covariate-adjusted analysis of the primary endpoint using a
      Cox proportional hazards model will be performed as a supportive analysis. The hazard ratio
      and its corresponding 95% confidence interval will be estimated. Subjects withdrawing from
      the study early (other than for withdrawal of consent) will be followed for potential
      development of the primary endpoint. Subjects completing the study and not experiencing the
      composite event will be censored.

      Secondary Endpoint Analysis: All time-to-event secondary endpoints will be analyzed similarly
      to the primary endpoint.

      Sample Size: Hazard rates have been estimated for the placebo and ICD groups using subjects
      from a variety of databases (including the Echos database and the publication of Definite).
      Assuming a 24-month enrollment period and a 36 month follow-up period (resulting in a 5-year
      study with a minimum treatment period of 3 years and approximately a median survival time of
      60 months), a total of 812 subjects will provide a 80% power with a 2-sided significance
      level of 5% for detecting a reduction in hazard of 25%.

      Safety Summary: The subject incidence of adverse events will be tabulated for each group.
      Adverse events related to ICD implantation will be summarized. During the trial inappropriate
      shocks will be summarized.

      Data Monitoring Committee: An independent Data Monitoring Committee consisting of members
      with relevant expertise will be assembled prior to study commencement. This committee will
      periodically review safety data.

      Endpoint Classification Committee: An external Endpoint Classification Committee will
      adjudicate death as sudden or non-sudden throughout the study.
    

Study Phase

Phase 4

Study Type

Interventional


Primary Outcome

All cause mortality

Secondary Outcome

 Cardiovascular death

Condition

Heart Failure

Intervention

ICD

Study Arms / Comparison Groups

 A
Description:  Heart Failure nonischemic etiology

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Device

Estimated Enrollment

1000

Start Date

February 2008

Completion Date

July 2016

Primary Completion Date

July 2016

Eligibility Criteria

        Inclusion Criteria:

          -  ≥ 18 years of age at the time of screening.

          -  Documented non-ischemic HF with an LVEF ≤ 35%.

          -  NYHA class II-III. If patients are planned for an implantation with a biventricular
             pacemaker NYHA class IV patients will be accepted for the trial.

          -  Before any study-specific procedure, including assessments for screening, the
             appropriate written informed consent must be obtained (see section 12.1).

          -  NT-proBNP above 200 pg/ml (see appendix D).

        Exclusion Criteria:

        To be eligible for this study, subjects must not meet any of the following criteria:

          -  Uncorrected congenital heart disease or valve obstruction, obstructive cardiomyopathy,
             active myocarditis, constrictive pericarditis, untreated hypothyroidism or
             hyperthyroidism, adrenal insufficiency, active vasculitis due to collagen vascular
             disease.

          -  On the urgent waiting list for a heart transplant (UNOS category 1A or 1B, or
             equivalent). Patients on the non-urgent waiting list for a heart transplant (UNOS
             category 2 or 7, or equivalent) are eligible for inclusion in the study.

          -  Recipient of any major organ transplant (eg, lung, liver, heart or kidney).

          -  Receiving or has received cytotoxic or cytostatic chemotherapy and/or radiation
             therapy for treatment of a malignancy within 6 month before randomisation or clinical
             evidence of current malignancy, with the following exceptions: basal or squamous cell
             carcinoma of the skin, cervical intraepithelial neoplasia, prostate cancer (if stable
             localized disease, with a life expectancy of > 2.5 years in the opinion of the
             investigator).

          -  Known to be human immunodeficiency virus positive with an expected survival of less
             than 5 years due to HIV.

          -  Renal failure treated with dialysis.

          -  Recent (within 3 months) history of alcohol or illicit drug abuse disorder, based on
             self-report

          -  Any condition (eg, psychiatric illness) or situation that, in the investigator's
             opinion, could put the subject at significant risk, confound the study results, or
             interfere significantly with the subject's participation in the study.

          -  Unwilling to participate.
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Lars Køber, MD, D.Sci, , 

Location Countries

Denmark

Location Countries

Denmark

Administrative Informations


NCT ID

NCT00541268

Organization ID

2007-005606-45


Responsible Party

Sponsor

Study Sponsor

Danish Study Group

Collaborators

 Danish Heart Foundation

Study Sponsor

Lars Køber, MD, D.Sci, Study Chair, Department of Cardiology, Rigshospitalet.


Verification Date

June 2016