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.

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.

The long-term risk of smoking in diabetic patients with stable ischemic heart disease treated with intensive medical therapy and lifestyle modification.

Introduction The long-term risk of smoking in diabetic patients with stable ischemic heart disease (SIHD) is unknown. We sought to analyze the impact of smoking on outcomes of diabetic patients with SIHD when other cardiovascular risk factors are being aggressively treated. Methods The Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial randomized 2368 diabetics with SIHD to intensive medical therapy (IMT) with prompt revascularization or IMT alone. Smoking status was obtained at baseline, 6 months, and 1, 2, 3, 4 and 5 years. The primary endpoint of interest was all-cause mortality. Results Of 2360 patients, 33.1% of patients never smoked, 54.4% were former smokers, and 12.5% were current smokers. The rate of all-cause mortality was greater for current (2.5 deaths/100 patient-years) and former smokers (3.1 deaths/100 patient-years) than never smokers (2.1 deaths/100 patient-years) (P = 0.007). Cardiac death, cardiovascular death, fatal or nonfatal myocardial infarction, and fatal or nonfatal stroke were not increased in current or former smokers compared with never smokers. Compared with never smokers, current smokers experienced a 49% increased hazard of death (Hazard Ratio (HR) 1.49, 95% Confidence Interval (CI): 0.97-2.29, P = 0.07) whereas former smokers had a 37% increased hazard of death (HR 1.37, 95% CI: 1.04-2.79, P = 0.02) when considering smoking status as a time-dependent variable and adjusting for factors that differed by smoking status. Conclusions Current and former smoking are associated with increased all-cause mortality in diabetics with SIHD but not with increased cardiovascular morbidity or mortality.