BARI 2D: Increased Risk Factor Control in Patients With Type 2 Diabetes Ups Survival
In patients with stable coronary disease and type 2 diabetes, controlling multiple cardiovascular risk factors with optimal medical therapy (OMT) over time can improve survival and reduce adverse events, according to post hoc analysis of the BARI 2D trial published in the August 18, 2015, issue of the Journal of the American College of Cardiology.
BARI 2D enrolled 2,368 patients who had both type 2 diabetes and stable CAD. After angiography but prior to randomization, patients were assigned by their physician to CABG (n = 763) or PCI (n = 1,605). Within these subgroups, patients were then randomized 1) to intensive medical therapy with or without early revascularization and 2) to insulin-sensitizing or insulin-providing therapy.
For the substudy, Vera Bittner, MD, MSPH, of the University of Alabama at Birmingham (Birmingham, AL), and colleagues followed 2,265 patients (mean age 62 years; 29% women) who attended 47,044 office visits over a mean duration of 5 years. Control of 6 prespecified risk factors was determined in each patient according to the following target values:
- Systolic blood pressure (BP) < 130 mm Hg
- Diastolic BP < 80 mm Hg
- Glycosylated hemoglobin (HbA1c) < 7%
- Triglycerides < 150 mg/dL
- Non-HDL cholesterol < 130 mg/dL
Younger patients and those outside of North America tended to have fewer risk factors in control. Between 40% and 68% of patients met individual risk factor targets, with only 7% meeting all 6 risk factor goals.
Greater Control Linked to Better Outcomes
The mean number of risk factors in control increased from 3.5 at baseline to 4.2 after 5 years (P < .0001). The greatest change in medication use occurred within the first year, with aspirin and lipid-lowering drugs being prescribed more often over this time and their levels evening out over follow-up. Improvements for all risk factors were seen, except for smoking prevalence (which was maintained) and hemoglobin levels (which worsened). At 5 years, more than three-quarters of patients had at least 4 risk factors in control, but only 15% had all 6 in check.
Over the study period, the Kaplan-Meier rates of total mortality and cardiovascular disease events (death, MI, and stroke) were 11% and 22%, respectively. There was no relationship between the number of risk factors in control at baseline and the likelihood of subsequent death (P = .36) or the composite endpoint (P = .22).
However, risk factor control at 1 year did carry weight—those with 0 to 2 risk factors in control were twice as likely to die and 1.7 times more likely to experience death, MI, or stroke than those with all 6 risk factors in control.
Additionally, the overall number of risk factors in control over 5 years was related to both death (global P = .0010) and the composite outcome (global P = .0035) after adjustment for baseline control. “This model suggested a J-shape,” according to the authors, in that patients with 6 risk factors in control compared with 5 had nonsignificantly higher risks of death and the composite endpoint.
In an exploratory analysis using less stringent definitions of systolic BP and HbA1c control, this uptick in risk between 5 and 6 factors disappeared, “suggesting that aggressive control of [these particular risk factors] is associated with increased risk,” Dr. Bittner and colleagues write.
Additionally, when patients were stratified by cardiac randomization group, those who had early revascularization in addition to OMT alone were more likely to benefit from risk factor control, though the interaction between treatment and the number of factors controlled was not significant.
Implications for the Wider Diabetes Population
“These observational data suggest that patients with [CAD and type 2 diabetes] require multiple [risk factor] interventions, including management of systolic BP and HbA1c, to avoid undertreatment and overtreatment,” the study authors write. “[Risk factor] control among [these patients] has improved, but treatment targets in effect during BARI 2D are often not achieved…. BARI 2D data show that [risk factor] treatment goals are achievable by using evidence-based, protocol-guided therapy with dedicated personnel.”
The fact that the number of baseline risk factors in control did not seem to affect outcomes but the number in control after 1 year did has several possible explanations, the investigators say, including the potency of pharmacological interventions initiated after randomization (eg, statins and antihypertensive agents).
Lessons learned from this population could result in better prognoses for diabetes patients in the general population today “with appropriate resource allocation,” Dr. Bittner and colleagues write.
“These analyses also suggest that there is a plateau of benefit at 5 [risk factors] under control [and] that overcontrol of systolic BP, but not HbA1c, could mediate this phenomenon.”
OMT for All
In an accompanying editorial, David J. Maron, MD, of Stanford University School of Medicine (Stanford, CA), and William E. Boden, MD, of Albany Medical Center (Albany, NY), say that the study is “important because it has been assumed that OMT in recent [stable ischemic heart disease] strategy trials reduced clinical events (assumed because there were no comparison groups that did not receive OMT), but until now the evidence to support this assumption has been lacking.”
The current analysis, “although post-hoc and exploratory, [illustrates] the impact of good multiple risk factor control versus poor or moderate risk factor control in [stable ischemic heart disease] patients with diabetes by using adjudicated endpoints,” they write.
The editorialists point out that successful control of multiple risk factors in this patient group is relatively infrequent, as demonstrated by the REGARDS study and in a pooled analysis from COURAGE, BARI 2D, and FREEDOM. “The remarkable observation in the present report is the significantly better survival (a 50% lower mortality rate) among patients who achieved good risk factor control in a trial that found no survival benefit from revascularization. Although the study was not a randomized comparison of OMT versus no OMT, the conclusions are convincing and consistent with evidence from decades of careful epidemiological research,” they write.
The ongoing ISCHEMIA trial testing the benefit of elective revascularization might prove differently, Drs. Maron and Boden comment, but “these data are compelling and argue persuasively that all patients with [stable ischemic heart disease] should receive OMT, regardless of whether they undergo revascularization.”
1. Bittner V, Bertolet M, Felix RB, et al. Comprehensive cardiovascular risk factor control improves survival: the BARI 2D trial. J Am Coll Cardiol. 2015;66:765-773.
2. Maron DJ, Boden WE. Why optimal medical therapy should be a universal standard of care [editorial]. J Am Coll Cardiol. 2015;66:774-776.
- Meta-analysis: PCI Adds No Benefit to Medical Therapy in Patients with Proven Ischemia
- Risk Factor Control Linked to Better Outcomes After Peripheral Intervention
- BARI 2D: Sub-analyses Explore Nuances of Revascularization vs. Medical Therapy Alone
- BARI 2D was funded by Abbott Laboratories, Astellas Pharma US, GlaxoSmithKline, Lantheus Medical Imaging, Merck, the National Heart, Lung, and Blood Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, and Pfizer. Supplemental funding and support for the trial also were provided by multiple drug and device companies.
- Dr. Bittner reports receiving research support from Amgen, Bayer Healthcare, Janssen Pharmaceuticals, the National Institutes of Health, Pfizer, and Sanofi; and serving on advisory panels for Amgen and Eli Lilly.
- Drs. Maron and Boden report receiving NIH grant support for the ISCHEMIA trial.