Increased Hazard of Myocardial Infarction With Insulin-Provision Therapy in Actively Smoking Patients With Diabetes Mellitus and Stable Ischemic Heart Disease: The BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) Trial

Abstract

Background: In the BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) trial, randomization of diabetic patients with stable ischemic heart disease to insulin provision (IP) therapy, as opposed to insulin sensitization (IS) therapy, resulted in biochemical evidence of impaired fibrinolysis but no increase in adverse clinical outcomes. We hypothesized that the prothrombotic effect of IP therapy in combination with the hypercoagulable state induced by active smoking would result in an increased risk of myocardial infarction (MI).

Methods and results: We analyzed BARI 2D patients who were active smokers randomized to IP or IS therapy. The primary end point was fatal or nonfatal MI. PAI-1 (plasminogen activator inhibitor 1) activity was analyzed at 1, 3, and 5 years. Of 295 active smokers, MI occurred in 15.4% randomized to IP and in 6.8% randomized to IS over the 5.3 years (P=0.023). IP therapy was associated with a 3.2-fold increase in the hazard of MI compared with IS therapy (hazard ratio: 3.23; 95% confidence interval, 1.43-7.28; P=0.005). Baseline PAI-1 activity (19.0 versus 17.5 Au/mL, P=0.70) was similar in actively smoking patients randomized to IP or IS therapy. However, IP therapy resulted in significantly increased PAI-1 activity at 1 year (23.0 versus 16.0 Au/mL, P=0.001), 3 years (24.0 versus 18.0 Au/mL, P=0.049), and 5 years (29.0 versus 15.0 Au/mL, P=0.004) compared with IS therapy.

Conclusions: Among diabetic patients with stable ischemic heart disease who were actively smoking, IP therapy was independently associated with a significantly increased hazard of MI. This finding may be explained by higher PAI-1 activity in active smokers treated with IP therapy.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00006305.

Keywords: coronary artery disease; diabetes mellitus; insulin; myocardial infarction; smoking.

© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

Figures

Figure 1

A, Rates of freedom from fatal or nonfatal MI in active smokers (smoking status as a time‐dependent variable) with IS vs IP therapy. B, Rates of freedom from fatal or nonfatal MI in nonsmokers (smoking status as a time‐dependent variable) with IS vs IP therapy. IP indicates insulin provision; IS, insulin sensitization; MI, myocardial infarction.

Figure 2

A, Median (first, third quartiles) PAI‐1 antigen levels in active smokers and nonsmokers randomized to IP or IS therapy at baseline and at 12, 36, and 60 mo following randomization. B, Median (first, third quartiles) PAI‐1 activity levels in active smokers and nonsmokers randomized to IP or IS therapy at baseline and at 12, 36, and 60 mo following randomization. IP indicates insulin provision; IS, insulin sensitization; PAI‐1, plasminogen activator inhibitor 1.