Role of Primary Invasive Strategy and Revascularization in Diabetic Patients with Acute Coronary Syndromes

Diabetes Mellitus as a Major Risk Factor in Acute Coronary Syndromes

Diabetic patients are more likely to present with atypical symptoms, and in both ST-segment elevation and non–ST-segment elevation myocardial infarction the delay from onset of pain to clinical presentation is longer than in nondiabetic patients. ^{, ,} Moreover, diabetic patients presenting with ACSs are older, more often female, more often obese, and have more comorbidities, specifically hypertension and renal failure. ^{, ,} They also exhibit more complex coronary artery disease than patients without diabetes. In an analysis of the Euro Heart Survey on percutaneous coronary intervention (PCI), the number of patients with severely stenosed segments (> 70%) was significantly higher in patients with diabetes compared with patients without ACS. There was also a higher proportion of patients with left main disease and triple vessel disease as well as more type C lesions in patients with versus without diabetes.

Moreover, compared with nondiabetic ACS patients, those with diabetes exhibit increased short-term and long-term mortality. ^{, ,} In the Organization to Assess Strategies for Ischemic Syndromes (OASIS) registry, diabetes independently predicted 2-year mortality (relative risk 1.52, 95% confidence interval [95% CI] 1.38-1.81, P < 0.001). Subsequently, GRACE reported odds ratios (ORs) for in-hospital death in patients with versus without diabetes of 1.48 (95% CI 1.03-2.31) for ST-segment elevation myocardial infarction (STEMI), 1.14 (95% CI 0.85-1.52) for non–ST-segment elevation myocardial infarction (NSTEMI), and 1.14 (95% CI 1.02-1.95) for unstable angina. Similar results were obtained in a pooled analysis of 62,036 patients of 11 independent ACS trials of the Thrombolysis in Myocardial Infarction (TIMI) study group. In this analysis, diabetes was significantly and independently associated with 30-day and 1-year mortality, both in NSTEMI ACSs and STEMI (hazard ratios [95% CI] 1.65 [1.30-2.10] and 1.12 [1.08-1.38], respectively). The association of diabetes mellitus with poor survival after ACSs is stronger in women than in men.

Hyperglycemia on admission for ACSs also strongly predicts mortality independent of the presence or absence of diabetes mellitus. Thorough analyses of the GRACE trial have suggested that fasting glucose levels were better predictors for in-hospital and 6-month survival than the presence or absence of diabetes. Hyperglycemia on admission has been considered to be a strong reflection of an acute stress response. The close relation between glucose metabolism and outcome of ACSs is also reflected by the recent demonstration of an independent association of hemoglobin A1c (HbA1c) with long-term (3.3 ± 1.5 years) mortality after PCI in STEMI.

The association between impaired glucose tolerance and survival after ACSs is less clear. Whereas an earlier study demonstrated an association between impaired glucose tolerance and poor survival, a more recent analysis of the Euro Heart Survey on diabetes and the heart did not find any significant independent predictive value of impaired glucose tolerance with respect to survival.

In addition to its impact on mortality, the presence of diabetes also increases the risk of heart failure as well as renal failure during the in-hospital phase by approximately twofold in patients presenting with STEMI or NSTEMI ACSs, as shown by the GRACE study, and the risk of bleeding complications by approximately one quarter, as shown by the CRUSADE trial. The risk of recurrent myocardial infarction and heart failure is also increased during long-term follow-up. ^{, ,} Moreover, in a large Danish registry, target lesion revascularization after PCI for ACSs was more often needed in patients with versus without diabetes (adjusted hazard ratio 1.55, 95% CI 1.14-2.11). Even more important, an analysis from the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial revealed that the risk of stent thrombosis after placement of a drug-eluting stent in acute myocardial infarction was tripled in patients with diabetes. In the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial, patients with stent thrombosis more frequently had insulin-requiring diabetes than patients without stent thrombosis, with similar outcomes for drug-eluting and bare metal stents.

Benefits of a Primary Invasive Strategy

ST-Segment Elevation Myocardial Infarction

In acute myocardial infarction, fibrinolysis compared with conservative treatment reduces the mortality by 18% as shown by a meta-analysis of randomized trials in this setting. In addition to this benefit, coronary reperfusion by primary PCI reduces in-hospital mortality by an additional 37%. Moreover, PCI compared with fibrinolysis reduces the risk of reinfarction and stroke, particularly of hemorrhagic stroke. The initial benefit has been maintained during a long-term follow-up.

The specific role of primary PCI compared with fibrinolysis for myocardial infarction in diabetes mellitus was addressed by a pooled analysis of individual patient data (N = 6315) from 19 trials comparing primary PCI with fibrinolysis. As compared with fibrinolysis, the benefit of primary PCI with respect to 30-day survival was numerically larger in patients with versus without diabetes ( Fig. 22-1 ). Nevertheless, a statistically significant P value for interaction was not achieved (P _int = .24). The ORs comparing primary PCI with fibrinolysis with regard to death and recurrent myocardial infarction were similar in patients with and without diabetes (OR [95% CI] 0.52 [0.35-0.77] and 0.51 [0.42-0.61], respectively), whereas those for stroke were numerically more favorable in patients with diabetes (ORs [95% CI] 0.40 [0.16-0.99] and 0.58 [0.39-0.86], respectively), yet without reaching a significant interaction P value. Because the incidence of death, recurrent myocardial infarction, and stroke was higher in patients with versus without diabetes irrespective of the treatment modality, similar risk ratios resulted in larger absolute risk reductions. In summary, this meta-analysis demonstrates that primary PCI in patients with diabetes is at least as safe and efficacious as in patients without diabetes and may even confer a larger absolute benefit over fibrinolysis than in patients without diabetes. Nevertheless, the increased mortality associated with diabetes remained. This may be attributed to differences in baseline patient characteristics, but possibly also to less effective microvascular reperfusion. Analyses of the Enhanced Myocardial Efficacy and Removal by Aspiration of Liberated Debris (EMERALD) trial suggested impaired microvascular reperfusion despite similar vessel patency in patients with versus without diabetes. This was evidenced by significantly inferior ST resolution and a significantly lower proportion of patients achieving a myocardial blush grade of 2 or 3 among the diabetes subset of patients.

Non–ST-Segment Elevation Acute Coronary Syndromes

For high- to intermediate-risk patients with NSTEMI ACSs, current guidelines recommend an invasive strategy that involves coronary angiography and revascularization irrespective of the primary success of medical treatment. ^, This recommendation is supported by a number of trials. A meta-analysis published in 2005 concluded that the invasive strategy, although increasing the risk of in-hospital death and myocardial infarction (early hazard), significantly reduced death and myocardial infarction by 18% (95% CI 2%-42%) during the entire follow-up, ranging from 6 months to 2 years in various studies. Some of the studies included in this meta-analysis, however, were not contemporary because of marginal use of stents and low-level use of antiplatelet therapy. Nevertheless, a more recent meta-analysis of eight randomized controlled trials with contemporary management strategies demonstrated that the invasive strategy compared with the conservative strategy significantly reduced the composite of death, myocardial infarction, and rehospitalization because of ACSs at 1 year. Long-term benefits of the invasive strategy over 5 years were addressed by the FIR collaboration, who performed a meta-analysis of individual patient data from three major trials: Fragmin and Fast Revascularization During Instability of Coronary Artery Disease (FRISC II), Invasive Versus Conservative Treatment in Unstable Coronary Syndromes (ICTUS), and Randomized trial of a conservative treatment strategy versus an Interventional Treatment strategy in patients with unstable Angina (RITA 3). They found a significant reduction in the 5-year incidence of cardiovascular death and myocardial infarction (hazard ratio [95% CI] 0.81 [0.71-0.93], P = 0.02), which comprised a significant reduction in the incidence of myocardial infarctions (hazard ratio [95% CI] 0.77 [0.65-0.90], P = 0.01) and a trend toward decrease in cardiovascular death (hazard ratio [95% CI] 0.83 [0.68-0.01], P = 0.068). The FIR collaboration also stratified their meta-analysis cohort according to the extent of baseline cardiovascular risk into three groups with low, intermediate, and high risk. As shown in Figure 22-2 , the benefit of routine invasive strategy versus conservative strategy increased substantially with increasing risk, with an only minor benefit in low-risk patients, but a substantial, more than 10% absolute reduction in the 5-year incidence of death and myocardial infarction in high-risk patients. Among the variables included in this risk stratification, diabetes was the strongest multivariable predictor of risk, with a hazard ratio of 2.06 (95% CI 1.75-2.41).

Extending these findings by specifically addressing the role of diabetes mellitus, a collaborative meta-analysis of nine randomized trials comprising 9904 patients with non–ST-elevation ACSs, of whom 1798 (18.1%) had diabetes, was performed. In this meta-analysis, an invasive strategy was associated with a comparable relative reduction in death, myocardial infarction, or rehospitalization because of ACSs in patients with or without diabetes ( P _interaction =.83) ( Fig. 22-3 ). In diabetic patients, the meta-analysis revealed a significant reduction in the 1-year incidence of nonfatal myocardial infarction by the invasive as compared with the conservative strategy (relative risk [95% CI] 0.71 [0.55-0.92]) and of rehospitalization (relative risk [95% CI] 0.75 [0.61-0.92]). The efficacy of the invasive strategy in reducing recurrent nonfatal myocardial infarction and readmissions for ACSs even appeared to be larger in diabetic patients than in nondiabetic patients. Taken together, the results of this meta-analysis and the results of the FIR collaboration suggest that diabetic patients represent a subset of patients with NSTEMI ACSs who derive particular benefit from an invasive strategy.

Timing of Intervention