Nt-proBNP Guided Primary Prevention of CV Events in Diabetic Patients
Condition: Diabetes Mellitus; Heart Failure; Coronary Artery Disease
MeSH terms: Heart Failure; Coronary Artery Disease
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      Increased levels of NT-proBNP are known to increase the risk of cardiac events in diabetic
      patients. The other way around, patients with normal values have an excellent prognosis on
      short-term. We intend in our study to proof the hypothesis, whether it is possible to
      decrease NT-proBNP levels by intensified cardiac prevention care We aim those patients, who
      already have elevated levels, although no history of a cardiac disease. This decrease in
      NT-proBNP should be translated consequently in a decrease in cardiac events
    

Detailed description: 
      Patients with diabetes mellitus have a several-fold increased risk for cardiovascular disease
      (1-3, 16). Early diagnosis of theses diseases might prevent or at least postpone occurence of
      clinical manifest CAD and CHF. Multifactorial intervention, with a special interest on
      cardiac disease are proven to be beneficial for diabetic patients (4). Whether all patients
      benefit from a multi-drug supply including lipid lowering agents or antihypertensive drugs is
      not known. Thus, special population have to be defined, who profit most. E.g. the STENO-
      study population (4) consisted of patients with microalbuminuria. Microalbuminuria is known
      to be a good marker for outcome in this population (5). Consistently to the fact that
      microalbuminuria is a good marker for long-term outcome, the STENO-Investigators found a
      long-term benefit (average 7.8 years) for multi-factorial intervention in this special
      population. We recently found, that Nt-proBNP (Roche) is an excellent short-term predictor of
      cardiovascular events and death (10 months on average) in diabetics without a history of
      cardiac disease (6), which is already known for long-term (7-10). Patients above the normal
      range have a 10 % risk of first occurrence of a cardiac disease or death within short time.
      The advantage of Nt-BNP as a marker of risk is based on the fact, that it is increased in all
      cardiac disease dependent on the severity. Our data reveal that Nt-proBNP is superior to most
      known markers. The limitations of traditional surrogate marker of risk in diabetic patients
      was recently discussed in a joint statement of the American Heart and Diabetic Associations (
      Diabetes Care 2007 Januar).Whether lowering blood pressure or cholesterol is the optimal
      surrogate for therapeutic success is questionable. The Jikei Heart study (11) nicely shows a
      comparable decrease in blood pressure in several treatment groups, but a tremendous
      difference in outcome. The heart failure paradoxon demonstrates, that in this population
      patients with low blood pressure (12) or low cholesterol (13) are those with worse prognosis.
      And heart failure is immanent in diabetes. On the other hand a decrease in Nt-proBNP under
      therapy is known to be an excellent marker of outcome (14). We hypothesize, that including
      diabetic patients without a history of cardiac disease but increased levels of Nt-BNP will be
      an excellent short-term risk-population for prevention therapy. And, decreasing Nt-proBNP
      levels by optimized therapy will be a good marker for success to decrease the risk for future
      imminent events

      Patients will be randomized into two groups:

      Group A: Patients will be cared by a cardiologic unit. In accordance to the guidelines
      investigations will be performed to proof the existence of a manifest cardiac disease.
      Further on treatment will be tailored to minimize the individual risk profile in accordance
      to the guidelines (15). The main therapeutic focus will be a decrease in Nt-proBNP to 50% of
      the value at index time or below normal values. Secondly, a special focus will be set on
      optimizing anti-hyperglycemic therapy by a diabetologist (treatment to target). Further
      guideline-recommended medical treatment will be initiated if not yet started (if no
      contraindication exists all patients will receive oral anti-platelet therapy and lipid
      lowering medication). After obtained informed consent, patients will be investigated as
      clinical appropriate.

      Performance of echocardiography is mandatory to exclude aortic stenosis and to proof the
      existence of heart failure- as recommended by the guidelines. Group A:patients will receive
      scheduled visits monthly to optimize pharmacologic treatment.

      After optimization visits will be performed as clinical appropriate. In between patients have
      the opportunity to contact a responsible person and will be contacted additionally by
      telephone to proof therapeutic success. As clinical appropriate every visit laboratory sample
      will be drawn, demographic data, data about diabetic complications, pulse and blood pressure
      will be taken, to test, whether treating goals are reached (see CRF for details). After one
      year a scheduled visit is mandatory to obtain laboratory samples, pulse and blood pressure to
      proof final therapeutic success based on the goal parameter, cholesterol, Nt-pro-BNP, heart
      rate, blood pressure, HBA1c. Group B patients will be cared by the treating physicians as
      before. The patient and the physicians will be informed about the results of the
      investigations. After 1 year the patients receive a scheduled visit, where demographic data,
      data about diabetic complications, lab samples, ECG, and blood pressure will be taken.
      Anamnesis about hospitalization and drug prescription will be obtained. If a patient
      prematurely dies, data will be obtained by the treating physician or other responsible
      institutions. After two years only data about hospitalization and death will be obtained by
      telephone contact with the patient or the Melderegister in Group A and B. Observation period:
      1 year Cohort: 150 patients in each group

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Intervention name(s): Telmisartan, Bisoprolol; placebo
Intervention type(s): Drug; Drug
Intervention description(s): Dosage will be given dependent on the NT-pro-BNP levels. Up-titration will be performed until values are decreased to 50% or below normal cut-point; no intervention
Intervention MeSH terms: Telmisartan; Bisoprolol
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: Natriuretic peptide; Prognosis; Diabetes; Heart failure; Heart disease