**4. Diabetes and multivessel disease**

#### **4.1 Introduction**

*The Current Perspectives on Coronary Artery Bypass Grafting*

has been updated to a Class IIB, this could be done at the time of the primary index

*Algorithm for the Management of STEMI Patients With MVD. Modified from "The Management of MVD in STEMI: The Science and Art of Decision-Making in STEMI" (Feb 07, 2018) (Jacqueline E. Tamis-Holland,* 

The COMPLETE [60] (Complete vs. Culprit-only Revascularization to Treat Multi-vessel Disease After Primary PCI for STEMI) trial will compare the outcomes of approximately 3900 patients randomized to a strategy of staged multivessel PCI or culprit-only revascularization. The FULL REVASC [61] (FFR-Guidance for Complete Non-Culprit Revascularization) This trial intends to evaluate the CR in about 4000 patients with STEMI or not with very high risk in patients of MVD guided by FFR during the same hospitalization of the index procedure, to evaluate clinical results.

We were the precursors in the treatment of primary PCI in acute infarction as revealed by one of the first randomized trials with stent in acute myocardial infarction, our trial GRAMI [62]. In our daily practice we try to identify culprit vessel. If we have a territory where we find two vessels with critical lesions, we treat them. If the patient presents a critical lesion in another territory, we defer to perform it pre-discharge. We also consider the amount of territory that this vessel irrigates as

Multivessel PCI both during the index procedure and in stages in stable patients is safe and could lead to better long-term results at the expense of reducing emergency

well as its renal function when making the decision with the heart team.

or in stages during hospitalization or after discharge [48].

**3.8 Ongoing trials**

*MD, FACC; Addi Suleiman, MBBS).*

**Figure 2.**

**3.9 Our experience**

**3.10 Conclusions**

**18**

DM is a global health problem; about 10% of adult patients will have the disease, and a quarter of all revascularized patients globally have DM [63]. However, patients with DM compared to nondiabetics have more MACCE and chronic heart failure. In addition, these patients have diffused and segmental disease, which puts them at greater risk of events regardless of the revascularization selected [64, 65]. PCI is limited by a higher rate of repeat revascularization and a worse clinical outcome in DM patients than with nondiabetic patients. CABG carries a greater morbidity, increased length of stay, and longer recovery times. However, both strategies have been improved during the last decade. In particular, the introduction of DES [66] has dramatically changed the landscape for PCI, with a significant reduction in the rate of restenosis especially the so-called second-generation stents that can reduce the gap [67]. The FREEDOM trial [68] demonstrated lower rates of major adverse cardiovascular events in patients with stable ischemic coronary disease who were assigned to CABG than with PCI using DES of first generation, at long-term followup. It is evident that this pathology carries a high atherogenic risk, and its current treatment is of surgical competence. Even so, we think that patients with a low ERACI score [17] are good candidates for PCI treatment, and the arrival of the new generation stents of Ultrathin-Strut DES [69] could reduce the gap that was created.

#### **4.2 FREEDOM, critics, and main trials**

This trial [68] has become the most important among patients with diabetes and type of revascularization as well as follow-up, which was carried out worldwide in 140 centers that included 1900 patients with DM with MVD who were randomized to PCI with DES from first generation or CABG and its long-term follow-up of at least 5 years. The primary end point was the combined mortality events of all causes, nonfatal MI, and stroke, such as MACCE. The MACCE was significantly in favor of the CABG (18.7% vs. 26.6%, p < 0.005), there was also a decrease in the mortality of all causes (10.9% vs. 16.9%, p = 0.049), the stroke was lower in the PCI group (2.4% vs. 5.2%, p = 0.03), and the revascularization of the treated vessel was highly significant in favor of the CABG almost three more times on the first year of follow-up. The nonfatal MI was almost double with the PCI group [68]. When the quality of life was evaluated, it was although slightly significantly better with surgery than with PCI; this is due to the amount of repeated revascularization. So, this study showed strong data and full impact on revascularization guidelines [70]. Also with respect to FREEDOM, a study of hospital costs was carried out; it was also favorable for surgical treatment vs. percutaneous treatment [71].

The study showed that the outcomes were significantly lower among patients randomized to CABG (18.7%) than patients randomized to PCI (26.6%) (**Figure 3A**). A closer look at how these rates were derived is warranted. A total of 1900 patients (953 in the PCI group and 947 in the CABG group) were enrolled

**Figure 3.**

*A.B.C. FREEDOM trial results comparing ITT analyses. CABG, coronary arterial bypass graft surgery; ITT, intention-to-treat analysis; PCI, percutaneous coronary intervention. From "Critical appraisal of cardiology guidelines on revascularization: clinical practice" (David R Dobies and Kimberly R Barber).*

and randomized. However, for the 5-year outcome rates, the denominator was 752 for PCI and 781 for CABG. These numbers are not the group totals but rather the number of patients remaining at risk at the end of the study. The number of events and the number remaining at risk are independent of each other. A basic occupant of a rate is that the subjects in the numerator are included in the denominator. The percentages the authors report are not rates; they are ratios and are very misleading. Calculating the events among the number randomized in each group results in a relative difference of 26% that is less significant than reported (**Figure 3B**). We would have more confidence in these recalculated rates if the study included all subjects in the denominator and accounted for outcomes on all subjects. They do not include the 214 (11.3%) patients lost to follow-up for whom we have no outcome data. This study also experienced a significant differential in attrition by group. The CABG group had twice the patients lost to follow-up (14.9%) as the PCI group did (7.7%). Revising the comparison by adding in the lost patients as events and calculating it with an intention-to-treat analysis (attributing events to the group of original assignment), we get a very different picture for the 5-year outcome (**Figure 3C**). The relative 5% difference is not significant (p = 0.42). This finding is in line with the 2-year composite outcomes in which the study authors observed no difference in outcome rates (13.0% vs. 11.9%, p = 0.51). The 5-year finding is significantly biased by the differential FREEDOM trial results comparing ITT analyses [72]. Other points of FREEDOM, which used first-generation stents that are currently discontinued, we remember presented a high rate of thrombosis stent [73]. Also in the trial a great geographical disparity was observed, since this difference marked by the study only was able to observe in the United States and the other centers in the randomization, and there were no significant differences outside of North American centers [68]. VA CARDS trial [74] is a study of veteran hospitals in the USA, in 22 centers, and included diabetic patients with MVD and 198 patients to be revascularized to PCI with DES or CABG with a 2-year follow-up. The primary end point of the study was the combined death events of all causes and nonfatal MI. The study was stopped early due to very slow recruitment by enrolling a quarter of the pre-established patients, which did not produce the power necessary for the evaluation of events. Within the study, it was observed that mortality in the 2-year PCI group reached a very high number up to 21% vs. 5% for CABG, while mortality was very high in the CABG group up to 15% compared with 6.2% for the PCI. This study

**21**

*Current Status, Perspectives, and Future Directions of Multivessel Disease and Left Main…*

was inconclusive. CARDia trial was a randomized study conducted in 22 centers in the United Kingdom and 2 centers in Ireland. Where Diabetic patients with MVD and patients with complex single lesion defined as ostial or proximal lesion of the anterior descending artery, which did not include LMCA between PCI or CABG, BMS was initially used, but when available the DES were used with the Axicimab adjuvant. A total of 510 patients were included, in which the primary end point was the MACCE, which included death of all causes, MI, and stroke. The study was non-inferior and with a 1-year follow-up. After 1 year the MACCE was 10.5% in the CABG group and 13% in the PCI group (HR, 1.25; 95% CI, 0.75–2.09; p = 0.39); the mortality of all the causes were the same in both groups of 3.2% (HR, 0.98; 95% CI, 0.37–2.6; p = 0.97). Although the study did not reach non-inferiority, it made the

In this meta-analysis of the individual database of patients, where they analyzed 11 trials of patients with MVD followed in the long term, who were randomized to PCI or CABG, in the subgroup of patients with DM, it was observed that mortality was significantly higher in patients with PCI 15.7% than with CABG, which was 10.7% (p = 0.0001), while no differences were found among non-DM patients,

In the ERACI III registry [76] which included 3 cohorts of 225 patients in each group with multiple MVD and PCI with DES, PCI with BMS, and patients with CABG, we analyzed the results of the subgroup of diabetic patients in each group at 3 years of follow-up. The incidence of MACCE at 3 years was significantly higher in diabetics than nondiabetics (RR, 0.81 [0.66–0.99]; p = 0.018). Higher rates of death and nonfatal AMI and a trend toward increased TVR, among others, were the principal determinants of increased MACCE. When stratified by treatment modality, MACCE rates among diabetics 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). There was a nonsignificant trend toward more death and nonfatal MI among diabetics in the ERACI III-DES cohort (19.1%) than in the BMS (12.8%) or CABG (15.4%) arms of ERACI II. Just as in the FREEDOM trial, the only stents used were the first-generation stents. Another limitation is that it was not a randomized trial, but they were two well-

A total of 69 randomized trials that enrolled 24,015 diabetic patients with a total of 71,595 patient-years of follow-up satisfied our inclusion criteria. When compared with CABG (RR = 1.0), PCI with paclitaxel-eluting stent (RR = 1.57 [1.15–2.19]) or sirolimus-eluting stent (RR = 1.43 [1.06–1.97]) was associated with an increase in mortality. However, PCI with EES (RR = 1.11 [0.67–1.84]) was not associated with a statistically significant increase in mortality. In PCI with EES (RR = 1.31 [0.74–2.29]), the excess repeat revascularization was not statistically significant although the point estimate favored CABG. CABG was associated with numerically higher stroke. In patients with DM, evidence from indirect comparison shows similar mortality between CABG and PCI using EES. CABG was associated with numerically excess stroke and PCI with EES with numerically increased repeat

*DOI: http://dx.doi.org/10.5772/intechopen.89419*

PCI as feasible [75].

**4.4 Our experience**

followed cohorts.

revascularization [67].

**4.3 Meta-analysis of MVD and DM**

8.4% for CABG and 8.7% in the PCI group (p = 0.81) [43].

**4.5 Can newer generation DES bridge the gap?**

*Current Status, Perspectives, and Future Directions of Multivessel Disease and Left Main… DOI: http://dx.doi.org/10.5772/intechopen.89419*

was inconclusive. CARDia trial was a randomized study conducted in 22 centers in the United Kingdom and 2 centers in Ireland. Where Diabetic patients with MVD and patients with complex single lesion defined as ostial or proximal lesion of the anterior descending artery, which did not include LMCA between PCI or CABG, BMS was initially used, but when available the DES were used with the Axicimab adjuvant. A total of 510 patients were included, in which the primary end point was the MACCE, which included death of all causes, MI, and stroke. The study was non-inferior and with a 1-year follow-up. After 1 year the MACCE was 10.5% in the CABG group and 13% in the PCI group (HR, 1.25; 95% CI, 0.75–2.09; p = 0.39); the mortality of all the causes were the same in both groups of 3.2% (HR, 0.98; 95% CI, 0.37–2.6; p = 0.97). Although the study did not reach non-inferiority, it made the PCI as feasible [75].
