PONTIAC: NT-proBNP Selected Prevention of Cardiac Events in a Population of Diabetic Patients Without a History of Cardiac Disease: A Prospective Randomized Controlled Trial

Study Questions:

What is the impact of neurohormonal therapy in high-risk diabetic patients pre-selected using N-terminal pro–B-type natriuretic peptide (NT-proBNP)?

Methods:

The PONTIAC study was a randomized controlled trial of type 2 diabetic patients (n = 300) without pre-existing cardiac disease and NT-proBNP concentration >125 pg/ml. Participants were randomized into a control group that received usual care at specialized diabetes units and an intervention group managed at a university cardiac outpatient group. Patients in the intervention group had individualized visits for the initiation and up-titration of renin-angiotensin-system (RAS) antagonists and beta-blockers. In the intervention group, the dosage of the medications was increased until either NT-proBNP concentrations decreased by 50% or below normal value or a maximum recommended or tolerated dose was reached. The primary endpoint was hospitalization/death due to cardiac disease, and was assessed 2 years after the baseline visit.

Results:

In an unadjusted Cox regression model, the intervention group had a significant reduction in the primary endpoint (hazard ratio [HR], 0.351; confidence interval [CI], 0.127-0.975; p = 0.04), all-cause hospitalizations (HR, 0.657; CI, 0.465-0.927; p = 0.02), and unplanned cardiovascular hospitalizations or death (HR, 0.376; CI, 0.157-0.899; p = 0.03). RAS antagonists were up-titrated to 100% of the recommended dosage in 79% of cases in the intervention group compared to 42% in the control group (p < 0.0001). Beta-blockers were up-titrated to 100% of the recommended dosage in 51% of cases in the intervention group and in only 10% of cases in the control group (p < 0.0001). After 1 year and contrary to expectation, the control group NT-proBNP concentrations were comparable to concentrations in the intervention group.

Conclusions:

The authors concluded that up-titration of RAS antagonists and beta-blockers in diabetic patients preselected by a baseline NT-proBNP may be effective and safe in the primary prevention of death and cardiovascular events.

Perspective:

There is a paucity of clinical trials that examine the primary prevention of cardiovascular disease in diabetic patients. The authors investigated a strategy wherein high-risk diabetic patients were selected for up-titration of neurohormonal therapy on the basis of their baseline NT-proBNP. While this strategy may be effective, there are notable limitations to the current analysis. The improved outcomes in the intervention group were not associated with any significant decrease of NT-proBNP over time. The statistical analysis did not adjust for additional covariates, as acknowledged by the authors. The patients in the 'intensified' intervention group may have fared better because their therapy was better titrated to maximum recommended or tolerated doses. Thus, the findings from this study warrant further validation. In the interim, diabetic patients should receive adequate doses of recommended therapy.

Clinical Topics: Dyslipidemia, Prevention, Lipid Metabolism, Novel Agents

Keywords: Biological Markers, Renin, Cardiovascular Diseases, Transcription Factors, Diabetes Mellitus, Primary Prevention, Natriuretic Peptide, Brain


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