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

Coronary Artery Disease Clinical Trial

— PONTIAC  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00562952
• Other study ID #: 01/07
• Secondary ID: EK-Nr 391/2007
• Status: Completed
• Phase: Phase 2/Phase 3
• First received: November 23, 2007
• Last updated: May 2, 2012
• Start date: November 2007
• Est. completion date: December 2011

Study information

• Verified date: May 2012
• Source: Medical University of Vienna
• Contact: n/a
• Is FDA regulated: No
• Health authority: Austria: Federal Ministry for Health and Women
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 300
• Est. completion date: December 2011
• Est. primary completion date: December 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 19 Years to 95 Years

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Prevention

Related Conditions & MeSH terms

• Coronary Artery Disease
• Coronary Disease
• Diabetes Mellitus
• Heart Failure
• Myocardial Ischemia

Intervention

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
no intervention

Locations

Country	Name	City	State
Austria	General Hospital of Vienna Department of Endocrinology	Vienna
Austria	Medical University of Vienna	Vienna

Sponsors (2)

Lead Sponsor	Collaborator
Medical University of Vienna	Roche Pharma AG

Country where clinical trial is conducted

Austria, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Reduction in cardiac events		2	No
Secondary	Decrease in NT-pro-BNP in the treatment arm		1	No
Secondary	Reduction in NT-proBNP		1	No