Prognostic Impact of the Presence and Absence of Angina on Mortality and CV Outcomes in Patients With Type 2 Diabetes and Stable Coronary Artery Disease

Jul 12, 2013   |  Ronnie Ramadan, MD; Arshed A. Quyyumi, MD, FACC

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Editor's Note: Based on Dagenais GR, Lu J, Faxon DP, et al. Prognostic impact of the presence and absence of angina on mortality and cardiovascular outcomes in patients with type 2 diabetes and stable coronary artery disease: results from the BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) trial. JACC 2013;61:702-11. 

Background

This study was designed to determine whether the symptomatic status in patients with stable coronary artery disease (CAD) and type 2 diabetes mellitus (T2DM) affects long term outcomes free of death and myocardial infarction.

Methods

A post hoc analysis of the BARI 2D trial was performed. The study was designed to determine whether a strategy of prompt coronary revascularization and optimal medical therapy was superior to initial optimal medical treatment alone in patients with T2DM, stable CAD, and ischemia. Self-reported angina status was determined in 2364 patients, where ischemia was defined as either a positive electrocardiographic, echocardiographic, or myocardial perfusion stress test. Patients' coronary anatomy had to be suitable for either PCI or CABG and those with unstable symptoms in need of immediate revascularization, those with coronary revascularization within the previous 12 months, left main coronary disease, and class III or IV heart failure were excluded. Cardiac symptoms were classified as angina, angina equivalents such as dyspnea, or no symptoms.

Patients randomized to the prompt revascularization strategy had to have PCI or CABG within 4 weeks of randomization. Optimal medical therapy in both strategies consisted of lifestyle management, and pharmacological therapy to maintain HbA1c <7.0%, LDL <100 mg/dl, and blood pressure ≤130/80 mm Hg. Participants received individualized anti-anginal medications, and those who developed incapacitating angina or angina equivalent symptoms, had worsening ischemia or an acute coronary syndrome were revascularized during a follow-up period of 5.3 years.

Results

At study entry, 1434 (61%) patients had angina, 506 (21%) had angina equivalents, and 424 (18%) had neither. There were no differences among the 3 groups with respect to duration of diabetes, neuropathy score, lipid and glucose profiles, renal function, smoking status, previous MI, blood pressure, and use of aspirin, statins, and renin-angiotensin modulators. However, patients with angina were younger, more often women, and more frequently on nitrates and beta-blockers. During follow-up, patients in the angina group had higher use of nitrates and calcium channel blockers, and at five years, the rate of subsequent revascularization in the asymptomatic group was significantly lower at 25% as compared to 32% in the angina equivalent group, and 35% in the angina group.

The five-year mortality was similar in the three groups; 12%, 14% and 10% in patients with angina, angina equivalents, and asymptomatic patients, respectively. The five-year composite outcomes of all cause death, MI and stroke were also similar; 24%, 24% and 21%, respectively. After adjustment for confounders including severity of CAD and coronary revascularization, the 1.11 and 1.17 HRs for all-cause mortality in patients with angina and angina equivalents, respectively, compared to asymptomatic subjects were not significantly different. Finally, there were no differences in outcomes in subsets of patients with Class III or IV Canadian Class angina compared to those without, whether patients were randomized to initial medical therapy or to initial revascularization.

Conclusions

Patients with T2DM, stable CAD and ischemia are at similar risk of unpredictable adverse cardiovascular events of death, MI or stroke irrespective of their cardiac symptom status, suggesting that these patients should be managed similarly in terms of risk stratification and preventive strategies.

Perspective

The authors conclude that diabetic patients with stable CAD and ischemia should be managed similarly regardless of their cardiac symptoms. Although we agree with this statement that is based on one of the largest diabetic cohorts with ischemia studied to date, it is important to recognize the inherent limitations of this study due to its retrospective design, randomization of half of the subjects to immediate revascularization, imbalances in medical therapy and revascularization during follow-up, and limitations in generalizability of the findings because of enrollment selection.

CAD is the leading cause of death in T2DM and diabetics have higher rates of silent ischemia than the general population.1,2 Previous smaller studies in medically treated patients with mild to moderate CAD and silent myocardial ischemia suggested that their prognosis was similar to those with symptomatic ischemia.2-6 Even when the subgroup with more extensive CAD was analyzed separately in the BARI 2D cohort, no differences in outcomes were observed, suggesting that the more intensive medical therapy employed currently and particularly in this study, may have attributed to the better outcome observed.

In the DIAD study where randomly selected asymptomatic diabetics were screened with stress perfusion imaging, 16% were found to have mild or moderately severe ischemic defects. These subjects had a six-fold higher rate of adverse events during follow-up compared to those without ischemia, but their event rate was still modest and in the intermediate risk range.7 Importantly, equal number of adverse events occurred in those without ischemia. In BARI 2D, all patients were managed optimally with medications and lifestyle modifications, regardless of their cardiac symptoms. Nonetheless, silent ischemia in this population was associated with a significant rate of mortality despite optimal medical therapy. In clinical practice, physicians may be less aggressive in optimizing medical regimen and emphasizing lifestyle modifications in asymptomatic individuals, leading to even worse outcomes in these patients. Due to its design, these questions remain unanswered in BARI 2D. Moreover, whether routine screening for silent ischemia should be advocated in T2DM remains unresolved based on the BARI 2D results presented.

It is interesting to note that patients with angina of greater severity (Class III and IV) had similar risk of death and MI compared to those with none, atypical or mild symptoms, but their rate of revascularization was significantly higher during follow-up. Moreover, symptomatic patients had 7 to 15% higher rate of revascularization during follow-up compared to those who were asymptomatic, even though much of this difference was due to a higher PCI rate in the symptomatic subjects. Final analysis of the BARI 2D data showed that patients randomized to surgical revascularization had better outcomes than those who received medical therapy.1 The similar rate of events in the asymptomatic and symptomatic patients in this report should therefore be interpreted with caution because a greater proportion of symptomatic subjects were revascularized, and this may have improved their outlook.

Subjects were selected in the BARI 2D only if they had ischemia during stress testing, thus excluding those with symptoms without objective ischemia, and those who were asymptomatic and non-ischemic. Moreover, of the 4623 patients deemed to be suitable for randomization, just more than half were randomized. At least half of those not randomized were believed to require immediate revascularization by their physicians.8 In addition, patients with coronary anatomy deemed unsuitable for revascularization were excluded from this study. Moreover, it is likely that the vast majority of patients randomized to the revascularization arm became asymptomatic during follow-up. Thus, the true comparison of outcomes in the BARI 2D study based on presenting symptoms should be restricted to those randomized to initial medical therapy. These factors should be considered before generalizing these findings to all diabetics.

Finally, greater severity of ischemia during stress testing may be associated with worse long term outcome as has been observed in subgroup analyses of trials such as COURAGE, and have provided impetus for the ongoing ISCHEMIA study. In this study, analysis by severity of ischemia was not performed, and whether severe ischemia is more likely to be associated with symptoms was not studied.

In summary, it is reasonable to conclude that ischemia, whether symptomatic or asymptomatic, in diabetics with CAD has similar prognosis in subjects treated with optimal medical therapy when there is free availability of revasculariztion for symptomatic deterioration. Care should be taken not to extrapolate these findings to the general population with T2DM.

References

  1. Stamler J, Vaccaro O, Neaton JD, Wentworth D. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the multiple risk factor intervention trial. Diabetes care 1993;16:434-444.
  2. Janand-Delenne B, Savin B, Habib G, Bory M, Vague P, Lassmann-Vague V. Silent myocardial ischemia in patients with diabetes: Who to screen. Diabetes care 1999;22:1396-1400.
  3. Young LH, Wackers FJ, Chyun DA, et al. Cardiac outcomes after screening for asymptomatic coronary artery disease in patients with type 2 diabetes: The diad study: A randomized controlled trial. JAMA 2009;301:1547-1555.
  4. Valensi P, Paries J, Brulport-Cerisier V, et al. Predictive value of silent myocardial ischemia for cardiac events in diabetic patients: Influence of age in a french multicenter study. Diabetes care 2005;28:2722-2727.
  5. Albers AR, Krichavsky MZ, Balady GJ. Stress testing in patients with diabetes mellitus: Diagnostic and prognostic value. Circulation 2006;113:583-592.
  6. Lievre MM, Moulin P, Thivolet C, et al. Detection of silent myocardial ischemia in asymptomatic patients with diabetes: Results of a randomized trial and meta-analysis assessing the effectiveness of systematic screening. Trials 2011;12:23.
  7. Young LH, Wackers FJ, Chyun DA, et al. Cardiac outcomes after screening for asymptomatic coronary artery disease in patients with type 2 diabetes: The diad study: A randomized controlled trial. JAMA 2009;301:1547-1555.
  8. Bypass Angioplasty Revascularization Investigation 2 Diabetes Study G. Baseline characteristics of patients with diabetes and coronary artery disease enrolled in the bypass angioplasty revascularization investigation 2 diabetes (bari 2d) trial. Am Heart J 2008;156:528-536, 536 e521-525.

Keywords: Angina Pectoris, Echocardiography, Electrocardiography, Exercise Test


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