**4. Multivessel disease in diabetics**

Based on the current evidence, coronary artery bypass graft (CABG) is the treatment of choice for diabetic patients with multivessel disease [82]. However, since the inception of percutaneous coronary intervention, numerous trials have been designed to evaluate the efficacy of PCI versus CABG in patients with multivessel disease. In the following section, we will discuss the various trials that have compared surgical revascularisation to percutaneous intervention, beginning with balloon angioplasty and continuing to the modern DES era.

#### **4.1 Trials comparing CABG and BA**

Four trials designed to compare the efficacy of CABG versus BA have reported data on the subgroup of patients with diabetes mellitus: the EAST study, the BARI study, the CABRI trial and the RITA trial (**Table 2**) [83–86]. The only study that showed a significant benefit in survival of diabetic patients treated with CABG compared with BA, was the BARI trial. On the basis of these results, a clinical alert to US physicians from the National Heart, Lung, and Blood Institute, was published in Circulation 1995 and concluded that CABG should be the preferred treatment for patients with diabetes on drug or insulin therapy, who have multivessel coronary artery disease and require a first coronary revascularisation procedure.


#### **Table 2.**

*Randomised Controlled Trials comparing Balloon angioplasty versus CABG in patients with multivessel disease.*

#### **4.2 Trials comparing CABG versus PCI with bare metal stents**

There are four randomised trial that compared the outcomes from bypass surgery versus coronary stenting in patients with multivessel disease: the ARTS, the AWESOME trial, the SOS and the ERACI II trial. Only the first two trials analysed the diabetic subgroup separately, and neither showed any survival benefit. The ARTS (Arterial Revascularisation Therapy Study) trial reported a reduced event-free survival at 1 year in diabetics treated with stenting, as compared with those treated with CABG (63.4% vs. 84.4%, p = 0.001) [87]. This difference was largely due to a significant increase in repeat revascularisation in the stent group. Of note, the rate of complete revascularisation in patients who underwent PCI was only (70.5%) compared with those who had CABG (84.1%). Conversely, the rate of death and MI in diabetic were similar between groups (6.7% vs. 3.1%, p = 0.29 and 6.3% vs. 3.1%, p = 0.29, respectively). In addition, a trend towards an increase in the rate of cerebrovascular events was observed in the CABG group (1.8% vs. 6.3%, p = 0.009). At five years, there was no significant difference in mortality between the two groups. However, it was noted, that the rate of myocardial infarction was highest in the BMS arm, compared with CABG arm (11.0% vs. 5.2%). The AWESOME trial (Angina With Extremely Serious Operative Mortality Evaluation Trial) randomised 454 patients with multivessel disease to either CABG or stenting. Among diabetics, the respective CABG and PCI 36-month survival rates were comparable (72% for CABG vs. 81% for PCI) [88]. A collaborative analysis of data from ten randomised trials to compare the effectiveness of CABG with PCI (six trials used balloon angioplasty and four trials used with bare-metal stents), in patients with multivessel disease, showed that patients with diabetes (CABG, n = 615; PCI, n = 618), mortality was substantially lower in the CABG group than in the PCI group (HR 0.70, 0.56–0.87) [89].

In summary, despite these trials demonstrating a reduced need for subsequent revascularization following PCI with stents as compared to BA, the need for repeat revascularization remained significantly higher when compared to CABG in the diabetic population with multivessel disease. Moreover, the rate of myocardial infarction in diabetics was higher at long-term follow-up with the use of stents as compared to CABG. Thus, in the BMS era, revascularisation of diabetic patients with multivessel disease, CABG remained the first option of revascularization in patients suitable for surgery.

#### **4.3 Trials comparing CABG and DES**

The data available in the current era of DES comes from a combination of registry data, subgroup analysis from two randomised trials (the SYNTAX trial and the EXCEL trial) and two randomised trial performed specifically in diabetics patients. Beginning with the registry data**,** there are two multicentre registries that report data for diabetic patients treated with DES: the ERACI-3 and the ARTS 2 registries. Both registries compared a current cohort of patients with multivessel disease treated with drug-eluting stents with the historical cohort of patients from ERACI 2 and ARTS 1 trial respectively; treated with either CABG or conventional BM stenting. The ARTS 2 registry was a single arm trial that included 607 patients with multivessel disease treated with SES. The ARTS I and II studies included 367 diabetic patients (SES: 159, CABG: 96, and BMS: 112); at the 5-year follow up, the rate of major adverse cardiovascular and cerebrovascular events were significantly higher in patients treated with BMS (BMS 53.6% vs. CABG 23.4% vs. SES 40.5%; p < 0.01 for SES vs. BMS and SES vs. CABG). There was no significant difference in mortality among all 3 groups. There was an advantage of CABG over SES in

reducing repeat revascularisation procedures; interestingly revascularisation rate of patients treated with SES at 5 years approached that of patients treated with BMS although remained significantly lower. This "catch-up" phenomenon was not apparent in the non-diabetic population [90].

In the diabetic subgroup of ERACI-3 registry [91], MACCE rates at 3 years were 36.2% in the DES arm, 43.6% in the BMS arm, and 30.8% in the CABG group (p = 0.49). Of the components of MACCE, TVR was the only one that differed significantly across the three groups: drug-eluting stent (21.3%), bare metal stent (38.5%), and CABG (15.4%); p = 0.048. There was a non-significant trend towards more death and non-fatal MI among diabetics treated with DES (19.1%), than in the bare metal stent (12.8%) or CABG (15.4%) cohort of ERACI-2. Sub-acute late-stent thrombosis occurred more frequently in DES-treated patients, compared with BMS patients (P = 0.008).

Another registry [92] compared DES implantation with off-pump CABG. This study addresses the effect of DES versus off-pump CABG, on 1-year outcome of diabetic patients with multivessel disease and critical stenosis, involving the proximal left anterior descending coronary artery, who underwent elective myocardial revascularisation. Following propensity score analysis, adjusting for baseline differences between the 2 cohorts, DES increased the risk of 12-month MACCE (HR 1.88, 95% CI, p = 0.020). This was due to the higher rate for repeat revascularisation in the DES group (19% vs. 5%, HR 2.05, 95% CI, p = 0.001). In contrast, there was no difference in the rate of the composite endpoints of death, MI, and stroke (DES group 13%, CABG group 12%; adjusted analysis, HR 0.80, 95% CI, p = 0.40). On the other hand, the New York registry [93] showed a trend towards improved outcomes in diabetic patients treated with CABG (n = 3256), compared with DES (n = 2844) (or for death or MI at 18 months 0.84, 95% CI 0.69–1.01; p = 0.07).

The SYNTAX (Synergy between percutaneous coronary intervention with TAXUS and cardiac surgery) trial randomly allocated 1800 patients with left main and/or 3-vessel coronary artery disease to PES implantation or CABG. In the subgroup of patients with DM (n = 452), MACCE rate was significantly higher at 1 year with PES than with CABG (26.0% vs. 14.2%; RR 1.83 [1.22–2.73]; p = 0.003), at the expense of higher repeat revascularisation with PES (6.4% vs. 20.3%; RR 3.18 [1.77–5.71]; p < 0.001). Safety endpoint (death, stroke or MI), as well as symptomatic graft occlusion or stent thrombosis rates were comparable between treatment arms. Of note, in patients with SYNTAX score > 33, death rate was significantly higher with PES (13.5% vs. 4.1%; p = 0.04) [94].

There are two randomised trials comparing DES and CABG in patients with diabetes. The CARDIA trial (Coronary Artery Revascularisation in Diabetes) [95] is a non-inferiority trial, comparing optimal PCI with modern CABG, as a revascularisation strategy for patients with diabetes who have multivessel or complex single-vessel coronary disease. The 1-year results of the CARDIA trial did not demonstrate the noninferiority of PCI versus CABG for revascularisation of diabetic patients. At 1 year, the primary endpoint (composite of death, non-fatal MI and non-fatal stroke) was comparable between arms (10.5% in CABG vs. 13.0% in PCI arm; p = 0.39), only further revascularisation was significantly higher in the PCI arm (2% vs. 11.8%; p < 0.001). Although this study was the first randomised trial that compared the two revascularisation strategies in diabetic patients, it was underpowered for the primary composite outcome. Therefore, further information on optimal strategies for coronary revascularisation in diabetic patients is needed.

The FREEDOM trial (Future Revascularisation Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease) is a randomised trial, in which patients with diabetes and multivessel disease were randomly assigned to undergo multivessel PCI using DES versus bypass surgery and followed for up to 5 years. At 5 years follow-up, the primary outcome: a composite of death from any cause, nonfatal myocardial infarction, and nonfatal stroke occurred more frequently in the PCI group, compared with the CABG group (26.6% vs. 18.7%; p = 0.005). The benefit of CABG was driven by differences in rates of both myocardial infarction (P < 0.001) and death from any cause (P = 0.049). Cardiac death was not significant (p = 0.12). Stroke was more frequent in the CABG group than in the PCI group (2.4% vs. 5.2%; p = 0.03) [96].

The BARI 2 Diabetes (BARI 2D) [97] is a randomised, open, controlled, multicentre trial that compared optimal medical management with prompt revascularisation (PCI or CABG) in patients with type 2 DM and stable coronary disease. The primary endpoint was death from any cause. At 5-year follow-up, survival rate was comparable between groups (88%) with no difference in MACE or death. Patients treated with CABG showed much greater atherosclerotic burden and more lesions than the PCI stratum. Prompt revascularisation significantly reduced the MACE rate in those patients treated with CABG, largely because of a reduction in MI events, but not among those selected to undergo PCI as compared to optimal medical treatment. However, up to 42% of the patients allocated to optimal medical therapy required coronary revascularisation with PCI during the 5 years of follow-up [97].

A recent meta-analysis of 11 RCTs [98], involved 11,518 patients allocated to PCI or CABG. The 5-year all-cause mortality was 11.2% after PCI and 9.2% after CABG (HR 1.20, 95% CI 1.061.37; P = 0.0038). Among patients with DM, mortality rates were 15.7% in PCI and 10.1% in CABG (HR 1.44, 95% CI 1.201.74; P = 0.0001). Conversely, this difference was not found among non-diabetic patients.

There have been a number of studies comparing outcomes of CABG and PCI that involved the use of newer-generation DES. A large meta-analysis including 8095 patients with DM showed a significant reduction in MI, stent thrombosis, and MACE, with newer-generation everolimus-eluting stents, compared to first generation DES [99]. Data from the Randomised Comparison of Coronary Artery Bypass Surgery and Everolimus-Eluting Stent Implantation in the Treatment of Patients with Multivessel Coronary Artery Disease (BEST) study [100], showed that the outcomes were poorer in the PCI group, with the rate of the primary outcome of death, MI, or TVR at two years significantly higher (19.2 vs. 9.1%; *P* = 0.007). In a subgroup analysis of 505 patients with DM, in the Evaluation of XIENCE versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularisation (EXCEL) trial [101], the investigators reported the rate of the primary outcome of death, MI or stroke at three years occurred in 21.2% of patients in the PCI arm and 19.4% in the CABG arm (HR 1.04, 95% CI 0.70–1.55). In conclusion, is clear that we are yet to determine whether the newer generation DES will begin to narrow the divide favouring CABG for patients with DM and multivessel disease, and additionally, that further dedicated randomised control trials are needed.
