WP 03 is designed to characterise the prevalence, incidence, persistence and phenotype of obesity, cachexia and diabetes in patients with heart failure (HF).
It will make use of five cohorts; (i) a prospectively recruited cohort with heart failure (multi-centre); (ii) a prospectively recruited control cohort of patients with type 2 diabetes without heart failure (multi-centre); (iii) a control cohort of healthy subjects of similar age and gender distribution (multi-centre); (iv) a previously acquired, large, single centre, epidemiologically representative cohort of patients with suspected heart failure; and (v) a large prospective cohort of older diabetic patients screened for the presence of cardiac dysfunction or heart failure (single centre).
The primary objective of the prospective heart failure cohort is to understand the characteristics and mechanisms of disease progression related to diabetes, cachexia and obesity. It will also form the common entry point for all patients with heart failure studied within the other work packages ensuring consistency in the clinical assessment and characterisation across work packages focusing on vascular, cellular and molecular mechanisms. The control cohorts without heart failure will help define the extent to which observed abnormalities are due to heart failure or due to diabetes or obesity. It is unlikely that there will be cachexic patients in the intended control groups, but consideration will be given to identifying cachexic patients with respiratory disease or cancer.
The previously acquired, well characterised single centre cohort will compliment the prospective cohorts. Due to its longitudinal nature and comprehensive follow-up, it will answer many questions related to the prevalence, incidence and prognosis of diabetes, cachexia and obesity in patients with and without cardiovascular disease.
The prospective cohort of older diabetic patients will enable the prevalence of diagnosed and undiagnosed HF or cardiac dysfunction to be established. Once a patient has developed HF the pathogenic process may already be irreversible. Understanding the true level of undiagnosed cardiac dysfunction in diabetics will help to determine the best screening and treatment strategies for the future.
For the purposes of this study heart failure will be defined as; a diagnosis of heart failure based on symptoms (principally breathlessness on exertion or a prior history of pulmonary oedema and/or ankle swelling, especially if symptoms have improved with diuretics) PLUS NT-proBNP>400 pg/ml (patients with impaired renal function (eGFR<40ml/min/1.73m2) should have additional evidence of left ventricular or left atrial enlargement).
Workpackage Leader: HULL
Involved Partners: Charité, Wroclaw, IRCCS, St. Petersburg, Moscow MSU, Tomsk, Moscow CRC, Golnik, Zabrze
Recruitment:
HULL will be the central location for the co-ordination of WP03 and will, together with WP16, ensure the standardisation of recruitment procedures, common clinical assessments and database development. It is also the location of the retrospective suspected heart failure cohort and prospective diabetes screening cohort.
Component Study 1 (All Clinical Centres):
Prospective Characterization of Patients with HF and Their Natural History. All participating clinics (HULL, CHAR, WROC, ROME, CT, CRC, Bolnisnica Golnik, SCCS) will enrol patients into the prospective heart failure cohort. Patients will be recruited consecutively, where possible, with no pre-specified subgroups, however, we plan to enforce that 50% of recruited patients and control subjects are women. Patients already attending the clinic can also be included but should be clearly distinguished in the data-base from newly referred patients. Approximately 1600+ patients with heart failure will be recruited over 2-years (HULL 550; CHAR 200; SCCS 250; WROC 290; ROME 55; AC 100; CT 20 ; CRC 80; Bolnisnica Golnik 55). In addition 300+ diabetic controls without HF (but with similar age and sex distribution) will be recruited over 2-years (HULL 160; WROC 20; ROME 15; SCCS 10; AC 30; CT 20; CRC 30; Bolnisnica Golnik 15) as well as 150+ healthy subjects (with similar age and sex distribution) will be recruited (HULL 20; WROC 20; ROME 20; SCCS 10; AC 20; CT 20; CRC 20; Bolnisnica Golnik 20).
Characterisation:
All cases of HF / controls will have demographic data recorded, will complete the EuroHeart Failure Survey Questionnaire and EQ5D (to provide symptom profile and quality of life data) and have the following measured; height, weight (recorded using 50g scales), waist and hip circumference, blood pressure (sitting and standing), a 12-lead resting ECG and echocardiogram and 6-minute corridor walk test. They will have blood taken for routine biochemistry and haematology; including glucose, lipid profile, glycosolated haemoglobin (HbA1c), hsCRP and NT-proBNP (and aliquots stored for plasma bio-markers and DNA). Patients will also have fasting blood glucose measured.
Blood:
Routine biochemistry, haemotology and baseline NT-proBNP will be analysed using each centres local laboratories. In addition to the blood required for routine biochemistry, a total 45ml of blood will be taken for bio-bank storage in CHAR (for European clinics) and MSU (for Russian clinics). After centrifuging, this will produce 7.5ml of EDTA plasma, 7.5 ml of lithium heparin plasma, 10 ml of serum and 5ml of whole blood to be stored in 0.5ml aliquots. Samples will be organised using freezer proof labels with 2D barcode and unique anonymous identifiers. All clinical information and results from tests will be entered into a shared database located in HULL. Patients without a prior diagnosis of diabetes in whom fasting blood glucose or HbA1c are elevated above guideline levels will be recalled for an oral glucose tolerance test to make or reject a formal diagnosis of diabetes. Treatment should generally be by dietary means initially.
Follow-up:
Patients with NT-proBNP >400 pg/ml will be followed up clinically at 4-6 months to assess the effect of initial therapy and then at 16-18m and annual intervals there after (i.e. 28-30, etc) where time permits for a minimum follow-up of 18-months. Patients will undergo the same investigations as at baseline. Echocardiography will only be performed routinely at 4-months if clinically required. Patients in the control cohorts will be characterised at baseline and only followed-up where possible.
Component Study 2 (Hull Only):
Analysis of Patients Already Enrolled in a Large Prospective Longitudinal Clinical Epidemiology Study. The heart failure clinic in Kingston-upon-Hull has collected systematic data on all patients referred with suspected heart failure since 2001 including medical history and medication (including that for diabetes), symptoms, quality of life, height, weight, vital signs, echocardiograms, biochemistry (including random glucose, lipid profile and for many patients glycosolated haemoglobin), haematology, and neuro-endocrine profile. A plasma bank has also been retained although has been partially depleted by the measurement of novel biomarkers in recent years. Since 2004, patient's girth and body composition has also been measured. Patients with substantial impairment of left ventricular systolic dysfunction are routinely followed-up at 4 months, 12 months and annually thereafter but may be assessed at other times according to patient-need. These assessments mirror the baseline assessment. Unfortunately, we have not had the capacity (nor adequate diagnostic means) until now to enrol patients with heart failure and preserved left ventricular systolic function but intend to do so by the 2nd quarter of 2009. Nor do we have data on glucose tolerance tests or DEXA scans. More than 5,000 patients have been enrolled so far (2000 with confirmed HF) with more than 20,000 patient-years of follow-up and more than 1,000 deaths. This data set will be used to understand the prevalence, incidence and prognosis of patients with diabetes, cachexia and obesity; with and without heart failure.
Component Study 3 (Hull Only):
Screening of Diabetic Patients for Undiagnosed Cardiovascular Disease. Diabetic patients attending for annual review at diabetic and retinopathy clinics (~15,000 annually) will receive a screening questionnaire on heart failure symptoms, have blood taken for NT-proBNP measurement and an assessment of body habitus (height, weight and hip-waist ratio). Assuming a prevalence of undiagnosed cardiac dysfunction between 16% (based on local screening figures) and 50% (worst case) ; recruiting 4000 patients will give a margin of error of 1.0 - 1.4% in the prevalence estimate (assuming 95% C.I.)Patients with NT-proBNP >400 pg/ml will be designated as heart failure if they have symptoms and asymptomatic cardiac dysfunction (provided serum creatinine is <150umol/L) if they do not. Patients with values >400 pg/ml will be invited to attend the heart failure clinic for review as per Component Study 1. We anticipate 800 patients will be referred for cardiac assessment (assuming 16% un-diagnosed heart-failure, based on local screening figures). Outcomes for all patients will be followed by record linkage with hospital records for hospitalisation (and reasons) and death. There are no other hospitals providing emergency treatment in our region and our population is stable. Audit has shown that we identify more than 95% of all hospital admissions in this way.
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