Author + information
- †Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California
- ‡Department of Medicine, Samuel S. Stratton VA Medical Center, Albany Medical Center, and Albany Medical College, Albany, New York
- ↵∗Reprint requests and correspondence:
Dr. David J. Maron, Stanford University School of Medicine, 300 Pasteur Drive, Falk CVRC 289, Stanford, California 94305-5406.
- coronary artery bypass
- coronary artery disease
- diabetes mellitus
- percutaneous coronary intervention
- risk factors
A wise man, therefore, proportions his belief to the evidence.
—David Hume (1).
Recent randomized controlled trials of management strategies for patients with stable ischemic heart disease (SIHD) have used intensive pharmacological and lifestyle interventions, often referred to as optimal medical therapy (OMT), with or without initial revascularization (2–4). Although critics and supporters alike have attributed the lack of difference in death and myocardial infarction (MI) between treatment groups, in part, to the high quality of OMT used in all subjects, this “claim” has been an unproven assumption because these trials lacked a control group that did not receive OMT. An independent benefit conferred by intensive medical therapy has not, to date, been convincingly established.
In this issue of the Journal, Bittner et al. (5) report a post-hoc analysis from the BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) trial that used a creative method to evaluate the relationship between risk factor control, survival, and the composite endpoint of death, MI, or stroke, despite the absence of a no-OMT control group. As previously reported, not all BARI 2D subjects achieved their risk factor goals (6); in fact, only a small minority of patients achieved all of their treatment targets. In the present analysis, the investigators leveraged this spectrum of risk factor control by aggregating both treatment groups to assess the relationship between the degree of success with risk factor goal attainment and clinical outcomes.
Six risk factors were used in this analysis (5), and patients were considered “in control” if they achieved the following: no smoking; triglycerides <150 mg/dl; non–high-density lipoprotein cholesterol <130 mg/dl; glycosylated hemoglobin <7%; systolic blood pressure <130 mm Hg; and diastolic blood pressure <80 mm Hg. With the exception of the no-smoking goal, these trial definitions go beyond current Class I clinical practice guideline recommendations (7).
At baseline, only 7% of participants met all 6 risk factor goals (5). At 5 years, only 15% of patients achieved control of all 6 risk factors. Nevertheless, approximately three-quarters of patients had ≥4 risk factors in control during long-term follow-up. There was no relationship between the number of risk factors in control at baseline and subsequent death (the BARI 2D primary endpoint). In contrast, risk factor control at year 1 was strongly related to survival and cardiovascular outcomes after adjusting for the number of risk factors in control at baseline. Patients with only 0 to 2 risk factors in control had twice the risk of death (hazard ratio: 2.0; 95% confidence interval: 1.3 to 3.3; p = 0.0031) and 1.7 times the risk of the composite outcome (hazard ratio: 1.7; 95% confidence interval: 1.2 to 2.5; p = 0.0043) compared with patients who were able to achieve all 6 risk factors in control. There was no significant interaction between the initial treatment assignment (prompt revascularization or medical therapy) and the number of risk factors in control for either outcome.
This report (5) is important because it has been assumed that OMT in recent SIHD 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. With this analysis, although post-hoc and exploratory, the authors illustrate the impact of good multiple risk factor control versus poor or moderate risk factor control in SIHD patients with diabetes by using adjudicated endpoints. The findings are consistent with what might be expected on the basis of prior studies that compared aggressive multiple risk factor intervention with usual care (8,9). In addition, a recent publication from the SYNTAX (Synergy Between Percutaneous Coronary Intervention With TAXUS and Cardiac Surgery) trial investigators analyzed the effect of OMT in patients with complex coronary artery disease randomized to undergo percutaneous coronary intervention or coronary artery bypass grafting (10). OMT, which was not part of the trial intervention, was defined as the combination of at least 1 antiplatelet drug, statin, beta-blocker, and angiotensin-converting enzyme inhibitor or angiotensin receptor blocker; this is arguably a less stringent definition than reaching 6 risk factor goals. OMT, which was used in ≤50% of patients over 5 years, was associated with a 36% relative reduction in mortality at the 5-year follow-up compared with those not receiving OMT. The 36% relative reduction in mortality over 5 years associated with OMT was greater than the 26% relative reduction in mortality over 5 years associated with the randomized treatment assignment to coronary artery bypass grafting versus percutaneous coronary intervention in SYNTAX.
The present analysis (5) showed that when multiple risk factor goals were achieved in diabetic patients with SIHD, survival was improved and cardiovascular events were reduced, but control of all 6 treatment targets was achieved in only a minority of patients. Simultaneous attainment of multiple risk factor goals in patients with SIHD has previously been shown to be infrequent in the REGARDS (Reasons for Geographic and Racial Differences in Stroke) prospective cohort study (11) and in a pooled analysis from COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation), BARI 2D, and FREEDOM (Comparison of Two Treatments for Multivessel Coronary Artery Disease in Individuals With Diabetes) (6). 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.
Despite the ongoing uncertainty regarding the benefit of elective revascularization in patients with SIHD (currently being tested prospectively in the ISCHEMIA [International Study of Comparative Health Effectiveness with Medical and Invasive Approaches] trial ), we believe these data are compelling and argue persuasively that all patients with SIHD should receive OMT, regardless of whether they undergo revascularization. However, the use of OMT remains disappointingly low in patients with SIHD (10,13). The findings of Bittner et al. (5) provide powerful evidence that simultaneous control of multiple risk factors improves survival and reduces nonfatal MI and stroke. For that singular reason, OMT needs to be more widely embraced and utilized by clinicians as both a best medical practice and a universal standard of care in all patients with coronary artery disease.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
This article refers to work supported by National Heart, Lung, and Blood Institute grant U01HL105907, in-kind donations from Abbott Vascular, Medtronic, Inc., St. Jude Medical, Inc., Volcano Corporation, Arbor Pharmaceuticals, LLC, AstraZeneca Pharmaceuticals, LP, Merck Sharp & Dohme Corp., Omron Healthcare, Inc., and by financial donations from Arbor Pharmaceuticals LLC and AstraZeneca Pharmaceuticals LP. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute or the National Institutes of Health. Drs. Maron and Boden have received NIH grant support for the ISCHEMIA Trial.
- American College of Cardiology Foundation
- Hume D.
- Bittner V.,
- Bertolet M.,
- Barraza Felix R.,
- et al.,
- for the BARI 2D Study Group
- Farkouh M.E.,
- Boden W.E.,
- Bittner V.,
- et al.
- Fihn S.D.,
- Gardin J.M.,
- Abrams J.,
- et al.
- Haskell W.L.,
- Alderman E.L.,
- Fair J.M.,
- et al.
- Iqbal J.,
- Zhang Y.J.,
- Holmes D.R.,
- et al.
- Brown T.M.,
- Voeks J.H.,
- Bittner V.,
- et al.
- ↵New York University School of Medicine. International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA). Available at: http://www.clinicaltrials.gov/ct2/show/NCT01471522. Accessed June 9, 2015.