NT-proBNP Selected PreventiOn of cardiac eveNts in a populaTion of dIabetic patients without A history of Cardiac disease a prospective randomized trial

PONTIAC was designed as a proof of concept study. The number of patients
included was low and accordingly confirmation in a larger cohort is mandatory.
Secondly, the hypothesis that the treatment effect is restricted to patients
with high NT-proBNP levels cannot be deduced from the data. In this context a
concordant relationship between risk and treatment efficacy can be assumed.
This would result in an increasing number needed to treat up to a point of
ineffectiveness, depending on underlying risk. But, also a discordant
relationship is possible as side effects or over-suppression of neurohumoral
systems can lead to a preponderance of side effects over small or non-existing
treatment effects. Such a discordant treatment effect is called *interaction
effect* in statistical methodology. A cohort of patients without any evidence
of a cardiac disease, independent of NT-proBNP is mandatory to test for such
interactions. All these populations have to be evaluated in regard to safety
and efficacy. As both investigated groups of drugs are registered, the design
for a further study will be a post-authorization efficacy study (PAES) and a
post-authorization safety study (PASS) in distinct populations.

The purpose of this study is to evaluate the effect of high dose
RAS-antagonists and beta-blocker treatment for the primary prevention of
cardiac events in a population of patients with Type 2 diabetes mellitus (T2DM)
with no evidence of a preexisting cardiac disease. This will be done in
patients with NT-proBNP concentrations > 125pg/ml and the whole study
population. An additional aim is to demonstrate the dependency of the treatment
efficacy on the level of amino-terminal pro-B type natriuretic peptide (NT
proBNP) as a surrogate of imminent cardiac risk (so called interaction between
NT proBNP and treatment). A health economic analysis will objectify the impact
on health care costs in accordance to the endpoints.

This study is a randomized parallel group, active-controlled, two-arm,
long-term morbidity and mortality trial to evaluate the efficacy and safety of
high dose RAS-antagonist and beta-blocker therapy compared to standard diabetes
therapy in patients with diabetes without any history or sign of a cardiac
disease.

Echocardiography, ECG, bloodsamples and EuroQOL

Burden:
The time involved in this study, in the clinic is approximately 5 hours

Risk:
patiënt can not tolerate the full dose of the medication with signs of
bradycardia, clinically significant hypotension (symptomatic, increase of serum
Creatinine, hyperkalemia.
Potentiallly there are risks related to the insertion of a needle for the
bloodsamples, those are bruising, pain, dizziness and bleeding