Nt-proBNP Guided Primary Prevention of CV Events in Diabetic Patients (PONTIAC)

May 2, 2012 updated by: Martin Huelsmann, Medical University of Vienna

Nt-proBNP Guided Prevention of Cardiovascular Events in a Population of Diabetic Patients Without a History of Cardiac Disease

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

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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

  1. Stamler J., Vaqccaro O., Neaton JD., Wentworth D. Diabetes, other risk factors, and 12year mortality for men screened in the multiple risk factor intervention trial Diabetes Care 1993;16:434-44
  2. Kannel WB, McGee DL. Diabetes and cardiovascular risk factors: the Framingham study. Circulation 1979;59(1):8-13.
  3. Almdal T, Scharling H, Jensen JS, Vestergaard H. The independent effect of type 2 diabetes mellitus on ischemic heart disease, stroke, and death: a population-based study of 13,000 men and women with 20 years of follow-up. Arch Intern Med 2004;164(13):1422-6.
  4. Gaede P, Vedel P, Larsen N, Jensen G, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003;348:383-93
  5. Pambianco G., Costacou T., Orchard TJ The prediction of major outcomes of type 1 diabetes: a 12-year prospective evaluation of three separate definitions of the metabolic syndrome and their components and estimated glucose disposal rate: the Pittsburgh Epidemiology of Diabetes Complications Study experience. Diabetes Care 2007;30(5):1248-54
  6. Neuhold S, Nt-BNP as a short-term predictor of cardiovascular hospitalization or death in diabetic patients without history of cardiac disease compared to classical risk-factors EASD Meeting 2007 Amsterdam
  7. Dawson A; Jeyasslan S; Morris AD; Struthers AD. B-type natriuretic peptide as an alternative way of assessing total cardiovascular risk in patients with diabetes mellitus Am J Cardiol.2005 Oct 1;96(7):933-4
  8. Tarnow L; Plasma N-terminal pro-B-type natriuretic peptide and mortality in type 2 diabetes Diabetologia 2006;49: 2256-2262
  9. Gaede Hildebrandt P, Hess G, Parving HH, Pedersen O. P; Plasma N-terminal pro-brain natriuretic peptide as a major risk marker for cardiovascular disease in patients with type 2 diabetes and microalbuminuria Diabetologia 2005;48:156-163
  10. Bhalla MA; Prognostic role of b-type natriuretic peptide levels in patients with type 2 diabetes mellitus JACC 2004;44:1047-54
  11. Mochizuki S, Dahlöf B, Shimizu M, Ikewaki K, Yoshikawa M, Taniguchi I, Ohta M, Yamada T, Ogawa K, Kanae K, Kawai M, Seki S, Okazaki F, Taniguchi M, Yoshida S, Tajima N; Jikei Heart Study group. Valsartan in a Japanese population with hypertension and other cardiovascular disease (Jikei Heart Study): a randomised, open-label, blinded endpoint morbidity-mortality study. Lancet. 2007 Apr 28;369(9571):1431-9.
  12. Lee T, Chen J, Cohen D, Tsao L. The association between blood pressure and mortality in patients with heart failure Am Heart J 2006 Jan;151(1):76-83
  13. Rauchhaus M, Clark AL, Doehner W, Davos C, Bolger A, Sharma R, Coats AJ, Anker SD. The relationship between cholesterol and survival in patients with chronic heart failure. J Am Coll Cardiol 2003 Dec 3;42(11):1933-40

  14. Bettencourt P, Friões F, Azevedo A, Dias P, Pimenta J, Rocha-Gonçalves F, Ferreira A.

    Prognostic information provided by serial measurements of brain natriuretic peptide in heart failure. Int J Cardiol. 2004 Jan;93(1):45-8.

  15. Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: executive summary. The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD). Eur Heart J. 2007 Jan;28(1):88-136.

Study Type

Interventional

Enrollment (Actual)

300

Phase

  • Phase 2
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Austria
      • Vienna, Austria, 1090
        • Medical University of Vienna
      • Vienna, Austria, 1090
        • General Hospital of Vienna Department of Endocrinology

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

19 years to 95 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Age > 18 years
  • Known Diabetes mellitus > 6 months
  • Increased Nt-proBNP above 125pg/ml
  • Given informed consent

Exclusion Criteria:

  • Disease other than diabetes, with a life expectancy below 1 year
  • patients who suffer from chronic infection or malignant disease
  • Women in childbearing age without contraceptive
  • History of cardiac disease
  • systemic cortisone treatment
  • patients who are on chronic or acute hemodialysis, ultra filtration or peritoneal dialysis

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: 1
Patient will receive cardiac therapy to decrease NT-proBNP levels. This will be primarily RAAS-Antagonists and Betablocker. Blood pressure will be lowered to target values. A decrease of NT-proBNP is also known form life-style changes. Thus the patient will be educated to be trained
Drug: Telmisartan, Bisoprolol
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
Placebo Comparator: 2
Patients will be followed 2 years. Care will be given by the responsible unit ( Dept.of Endocrinology) as clinical appropriate. Event rates will be obtained. After one year NT-proBNP will be measured.
Drug: placebo
no intervention

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Reduction in cardiac events
Time Frame: 2
2

Secondary Outcome Measures

Outcome Measure
Time Frame
Decrease in NT-pro-BNP in the treatment arm
Time Frame: 1
1
Reduction in NT-proBNP
Time Frame: 1
1

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Medical University of Vienna

Collaborators

Roche Pharma AG

Investigators

  • Principal Investigator: Martin P Huelsmann, MD, Medical University of Vienna Dept.of Cardiology
  • Principal Investigator: Richard Pacher, MD, Medical University of Vienna Dept. of Cardiology
  • Study Director: Martin Clodi, MD, Medical University of Vienna Dept. of Endocrinology

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

November 1, 2007

Primary Completion (Actual)

December 1, 2011

Study Completion (Actual)

December 1, 2011

Study Registration Dates

First Submitted

November 23, 2007

First Submitted That Met QC Criteria

November 23, 2007

First Posted (Estimate)

November 26, 2007

Study Record Updates

Last Update Posted (Estimate)

May 3, 2012

Last Update Submitted That Met QC Criteria

May 2, 2012

Last Verified

May 1, 2012

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 01/07
  • EK-Nr 391/2007 (Other Identifier: Medical University of Vienna)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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