Dobutamine vs Adenosine CMR Study
Condition: Heart Failure; Coronary Artery Disease; Cardiac MRI
MeSH terms: Coronary Artery Disease; Myocardial Ischemia; Coronary Disease
Study type: Interventional

Summary: 
      This is a single centre, prospective diagnostic accuracy study to assess the comparative
      sensitivity of dobutamine versus adenosine for detection of severe non-infarct epicardial
      coronary artery stenosis in subjects with reduced LV EF ( EFed referred for clinical coronary
      angiography for investigation of symptoms or to establish the cause heart failure. Study
      participants will be identified from hospital angiography referral waiting lists, or already
      known with CAD and from heart failure outpatient clinics at Glenfield General Hospital.
      Clinical and CMR data will be collated on-site (at Glenfield General Hospital) from medical
      records stored and stress cardiac MRI scans at Glenfield General Hospital. The analysis will
      occur over a 12-month period following study commencement.
    

Detailed description: 
      Aim The primary aim of this study is to assess the comparative sensitivity of adenosine and
      dobutamine for detection of severe CAD in patients with HFrEF. Secondary aims are to evaluate
      how the addition of stress perfusion may alter management compared to CMR without stress.

      Primary hypothesis:

      In patients with HFrEF (EF≤40%), dobutamine perfusion has superior sensitivity to adenosine
      for the detection of non-infarct severe CAD (>70% epicardial coronary artery stenosis).

      Secondary hypotheses The addition of stress perfusion imaging to CMR cine and LGE imaging
      does not significantly increase the accuracy for determining whether the aetiology of HFrEF
      is due to CAD or not.

      The response to adenosine (haemodynamics/splenic T1) will be inversely related to markers of
      LV dysfunction/injury (high sensitivity troponin I/B-type natriuretic peptide) and directly
      to EF.

      Reduced myocardial perfusion reserve (<2.0) increases the accuracy of adenosine perfusion to
      detect CAD.

      The biphasic wall motion response to dobutamine is not specific for the detection of severe
      coronary artery stenosis.

      Experimental details and design of proposed investigation Design: prospective cross-sectional
      study. Subjects: participants will be recruited from the Cardiology Department at Glenfield
      General Hospital, Leicester, one of the largest secondary and tertiary care units in the UK.
      Patients referred for invasive coronary angiography to determine the cause of HFrEF or
      symptomatic angina and EF≤40% will be recruited. Patients will be contacted directly at
      hospital appointments or by letter after reviewing of case records to ensure eligibility.

      Inclusion criteria: 1. HFrEF (LV EF≤40%, consistent with recent guidelines for the diagnosis
      of HFrEF)[38] referred for investigation of CAD; 2. Age ≥18 years. Exclusion criteria: 1.
      Absolute contraindication to MRI. 2. Absolute contraindication to dobutamine OR adenosine; 2.
      Stage III-V renal disease (estimated glomerular filtration rate <30ml/min/1.73m2; 3. Previous
      coronary artery bypass grafting; 4. Unstable angina or MI within 6 weeks.

      Investigations:

        1. History taking and examination to confirm signs and symptoms of heart failure and obtain
           a current medical history.

        2. ECG to determine rhythm, ST-segment and conduction abnormalities. Venepuncture (20mL)
           for full blood count, biochemistry, high-sensitivity troponin I and B- type natriuretic
           peptide.

        3. CMR scanning performed at Glenfield Hospital on a dedicated NIHR 3T research scanner.
           The investigators have extensive experience of stress CMR for the assessment of CAD,
           including dobutamine stress. Each CMR study will be supervised by the fellow after
           appropriate training including safe administration of dobutamine. Patients will be asked
           to withhold beta-blocker therapy for 48 hours to minimise antagonism to dobutamine. For
           this study, The investigators will use newly installed software with dual-sequence
           perfusion that allows fully automated inline quantification of myocardial blood flow
           utilising advanced image reconstruction algorithms, Gadgetron, in conjunction with our
           collaborator (Dr Peter Kellman, NIH, Bethesda, USA). This sequence allows both visual
           analyses for perfusion defects and quantification of myocardial blood flow and perfusion
           reserve on a pixel by pixel basis. A modified protocol will be undertaken,
           incorporating:

      Cine functional assessment to determine ventricular volumes and function; Adenosine stress
      perfusion, dobutamine stress wall motion and perfusion, and rest perfusion imaging to assess
      qualitative perfusion defects, inducible wall motion abnormalities and myocardial perfusion
      reserve. Dobutamine will be reversed with intravenous metoprolol before undertaking LGE and
      then rest perfusion.

      Delayed contrast enhancement for assessment of LV fibrosis and evidence of previous
      myocardial infarction. The investigators did consider undertaking adenosine stress CMR and
      dobutamine stress CMR scans on separate days, to mitigate the effects of contrast remaining
      affecting perfusion quantification during dobutamine stress testing. However, this would
      double the expense of CMR scanning in the study and reduce the acceptability to potential
      participants. The investigators are confident that performing both adenosine and dobutamine
      stress in one CMR study will not have any material impact on image assessment, as there will
      be 20 minutes between the two stress sequences.

      All patients will have invasive coronary angiography performed as to clinical standards to
      assess for the presence of CAD, which will be performed within 4 weeks of CMR scanning.
      Fractional flow reserve will be performed as clinically indicated and given that this may be
      equally influenced by adenosine down-regulation is not mandated in the protocol.

      Image analysis: All imaging will be analysed blinded to patient details. CMR analysis will be
      undertaken by using dedicated software for research (cmr42, Circle Cardiovascular Imaging,
      Calgary, Canada). CMR studies will be divided into three series: i) cine and LGE images, ii)
      cine, adenosine stress and rest perfusion and LGE images, and iii) cine, dobutamine stress
      and rest and LGE images, and allocated a computer-generated random number identifier prior to
      analysis. Each of the 16 segments of the left ventricle will be scored for function,
      infarction, perfusion defects and contractile response as previously described. Qualitative
      analysis will be performed by the consensus of two readers (the fellow and Dr Arnold) and in
      cases of disagreement or uncertainty with a third observer (Prof McCann). Splenic switch-off
      will be assessed qualitatively and quantitatively with T1 mapping for evaluation of the
      adequacy of vasodilator stress with adenosine. The random number key will not be accessible
      to staff involved in the analysis until all analyses have been completed and the database has
      been locked. Image analysis of series I, ii and iii will be performed separately, at least
      two weeks' apart. Invasive angiography images will be anonymised and reported by a senior
      clinician or the fellow (after appropriate training and under supervision).

      Aetiology of heart failure: will be decided by a "gold" group consisting of an interventional
      cardiologist, heart failure specialist and cardiac imager (Dr Adlam, Prof Squire and McCann,
      respectively) who will be presented with all investigations, as per previous studies.

      Data handling: To reduce costs, the NIHR Leicester BRC staff have developed electronic
      databases using the validated and open source REDCap system and CiviCRM for management of
      recruitment of subjects into clinical studies, research, governance and monitoring. This
      infrastructure will be available during this programme of study. All imaging data will be
      entered into REDCap in a blinded fashion and will only be unblinded for statistical analysis
      when the database is locked. This will ensure the integrity of the data and any changes may
      be audited.

      Statistical analysis: Data will be examined for normality and summarised. Non-normally
      distributed data will be transformed to achieve normality prior to analysis. CMR image series
      will be compared by paired t-tests, Mann-Whitney and Chi-squared tests as appropriate. The
      sensitivities, specificities and accuracy of adenosine stress and dobutamine stress imaging
      for identifying non-infarct related ischemia will be compared. The kappa statistic will be
      used as a measure of agreement in diagnoses between series. Correlation coefficients will be
      assessed for adenosine response v markers of LV dysfunction.

      Power calculations The power calculation has been performed with the assistance of Dr C
      Nelson, Lecturer in Medical Statistics. From our pilot data, the sensitivity of adenosine for
      detecting non-infarct related myocardial perfusion abnormalities as our baseline standard is
      62%. The investigators estimate that the sensitivity of dobutamine for detecting perfusion
      abnormalities is 82%, as shown by Mordi et al. in patients with left bundle branch block at a
      maximum dobutamine dose of only 20μg/kg/min. Assuming the prevalence of CAD is 50% and
      dobutamine has sensitivity 20% higher than adenosine (Delta=0.82-0.62), 86 patients are
      required for 80% power at the 5% alpha level. To allow for technical issues with failure of
      either of adenosine, dobutamine or LGE or for patients who may decide not to proceed with
      invasive coronary angiography, investigators will recruit 100 patients. If all 100 patients
      completed the assessments investigators would have 80% power to detect an 18% increase in
      sensitivity with dobutamine.

      Bias and confounders The investigators will aim to recruit consecutive patients to avoid
      selection bias. Ascertainment bias will be minimised by robust blinding of CMR scans as
      outlined above. As the dobutamine and adenosine stress images will be acquired in the same
      patients, there is no confounding in selection between the two perfusion arms. The
      investigators are confident that the accuracy of the dobutamine perfusion will not be
      compromised by prior administration of contrast for adenosine perfusion due the relatively
      small dose used (0.05mmol/kg at 3T) and with the long time interval (~20mins) between
      contrast injections, allowing clearance.

      Timeline The investigators perform over 1000 clinical stress examinations and over 1200
      invasive coronary angiograms annually, many in patients meeting the inclusion criteria. The
      investigators aim to recruit a minimum of one patient per week and the study will be
      completed in under two years.

      The expected value of results This study will be the first to compare the diagnostic accuracy
      of adenosine versus dobutamine stress CMR for the detection of CAD in patients with HFrEF. If
      the results confirm that adenosine has poor sensitivity for the detection of CAD and that
      dobutamine is superior then the study will challenge the current paradigm of combined
      adenosine perfusion and CMR viability assessment. However before clinical practice is changed
      the investigators would plan to conduct a multicentre trial through BSCMR research group,
      which has a strong track record in multicentre clinical trials.
    

Intervention name(s): Stress Cardiac MRI
Intervention type(s): Diagnostic Test
Intervention description(s): Dobutamine and adenosine stress MRI
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Diagnostic