**4. Changing landscape in the treatment of CAD**

discussion of a hybrid approach with MIDCAB for the LAD and PCI of the other vessels. However, the evidence supporting this approach is still limited; the most recent European Society of Cardiology (ESC) Guidelines give a *Class IIb recommendation* to this approach *(Level of Evidence B) for those "patients with conditions likely to prevent healing after sternotomy"* [26]. This approach does have significant promise and further research is required before it is adopted

**3.5. Evidence of survival benefit for revascularization in stable ischemic heart disease**

The current framework for patient selection in treatment strategy for MVD is largely shaped by early studies comparing medical therapy and CABG. This body of evidence has been best synthesized by a meta-analysis performed by Yusuf et al in the Lancet in 1994 [27]. This metaanalysis was an individual patient data analysis of 2549 patients derived from three large randomized controlled trials, the Coronary Artery Surgery Study (CASS), Veterans Adminis‐ tration (VA) study and the European Coronary Surgery Study (ECSS) as well as four other smaller randomized studies [27]. The population studied consisted of patients with stable symptomatic coronary artery disease of a wide spectrum of severity [27]. However, only 10 percent were single vessel disease (1VD); the remainder consisted of MVD with 59.4% affecting

**Figure 1.** Survival curve for medical therapy versus coronary artery bypass grafting (CABG). Reproduced with permis‐

on a population level.

the proximal LAD [27].

sion from Yusuf S. et al. Lancet 1994. 344;8922:563-568

**(SIHD)**

320 Artery Bypass

Many of the earlier studies comparing surgical revascularization with medical therapy was during a period in cardiology where the BB and nitrates were the mainstay of medical therapy. Although antiplatelets were available, these were only taken by approximately 20% of the patients at the time [27]. It may hence be important to interpret these results in the context of current medical practice, which include contemporary treatments (standard secondary prevention with antiplatelets, statin therapy, BB and ACEi) that have all made further advancements in the survival and prognosis of patients with CAD [7].

ASA for secondary prevention has an estimated RRR of 18 percent in total serious vascular events (including stroke and major coronary event) with an **annual ARR of 1.5 percent**; the decrease in major coronary event (non-fatal myocardial infarction (MI) and cardiovascular death) is estimated at **annual ARR of 1.0 percent** [29]. As an adjunctive antiplatelet clopidogrel has further reduced death from cardiovascular causes, non-fatal MI and stroke in patients with Non ST elevation acute coronary syndromes (NSTEACS) with an **ARR of 2.1 percent**[30]. Most recently, newer agents such as prasugrel and ticagralor have both shown benefit compared to clopidogrel in patients with acute coronary syndromes (ACS). Prasugrel compared with clopidogrel in PCI treated ACS has demonstrated an **ARR of 2.2 percent** with regards to death from cardiovascular causes, nonfatal MI or non-fatal stroke over the 6-15 month follow up period [31]. Ticagralor has shown similar reduction in the same composite endpoint in patients with ACS over clopidogrel with an **ARR of 1.9 percent** [32]. In addition, ticagralor also showed an overall **reduction in all cause mortality with an ARR of 1.4 percent** [32].

BB's have a longstanding history in the management of CAD [7]. Although BB's can be used in patients post-MI with a normal ejection fraction (EF), the evidence for this is not as strong as that for those with significant Left Ventricular (LV) dysfunction [8]. It was previously shown that Carvedilol compared with placebo in patients with chronic heart failure (HF) and severe LV dysfunction (average EF 22-23 percent**) reduces all cause mortality with an ARR of 4.6 percent** [33].

The introduction of 3-hydroxyl-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors otherwise known as the "statins," has significantly improved the care of patients with coronary artery disease [34, 35]. Simvastatin 40mg orally daily compared to placebo in patients with known vascular disease was shown in the Heart Protection Study (HPS) to *reduce all cause mortality with an ARR of 1.8 percent* over a five year period [34]. This was paralleled with a **reduction of coronary death with an ARR 1.2%** [34].

[**0.23 95% CI 0.13-0.41) and [0.35, 95% CI 0.17-0.69]** respectively [24]. Finally, compared to even the zotarolimus second generation DES, the CoCr EES still demonstrated a robust reduction

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There have been numerous randomized studies comparing PCI with surgical revasculariza‐ tion in MVD. A recent systematic review including 10 major trials over and the individual data from over 7800 patients found similar mortality in patients treated with CABG (15%) compared to patients treated with angioplasty (16%) over median survival of 5.9 years (p=0.12) [45]. There was, however a significantly lower rate of death or repeat revascularization in those treated with CABG (9.9%) compared with those treated with PCI (24.5%) [45]. This suggests that in fact the major benefit seen in CABG over PCI in this comparison is a lower need for repeat revascularization and is paralleled by a lower incidence of angina in the CABG group (14%) compared to the PCI group (26%) at one year (p<0.0001) [45]. The major caveat to this data is that stenting (which is known to reduce restenosis rates) only represented 37 percent of the

Subgroup analysis revealed that patients with diabetes have overall *better survival* when treated with surgical revascularization than when treated with angioplasty **with an ARR of 7.7% over 5 years** [45]. More definitive data supporting the use of CABG in patients with diabetes will be presented in *Section 6.2.* Interestingly, there was also a graded age interaction that was significant (p=0.002) [45]. For patients younger than 55 years of age, mortality was lower with PCI (8%) than CABG (10%). In patients between ages 55-64, PCI and CABG had similar mortality rates at 15 and 14 percent respectively [45]. And for patients older than 65 years of age, CABG had a lower overall mortality (20%) compared with PCI (24%) [45]. Prior to this study, this interaction had not been previously reported and we can only speculate whether

Other subgroups did not prove to contribute any significant interaction to the overall treatment effect [45]. Six of the trials included had POBA as the main mode of PCI whereas four trials used BMS; neither of these groups had significantly different survival rates when compared with surgery [45]. There was no overall interaction contributed by the presence/absence of proximal LAD disease, 3VD, abnormal LV function, previous MI or unstable symptoms [45].

LV function has never been shown to have a significant interaction with mode of revasculari‐ zation (PCI versus CABG) with regard to survival. In fact, the majority of studies comparing PCI with CABG enrolled a low percentage of patients with abnormal LV function *(20 percent or less)* [45]. However, it has been considered an important variable that favors revasculariza‐ tion with surgery due to historical data showing that patients with significant LV dysfunction

**6. Factors favoring surgery as the mode of revascularization**

in stent thrombosis with an OR **[0.21, 95% CI 0.17-0.69]** at one year [24].

**5. PCI versus CABG in SIHD**

total angioplasty group [45].

the effect is a true function of age.

**6.1. LV dysfunction**

ACEi's have also been established to have a significant benefit towards long-term cardiovas‐ cular outcomes. It was shown in the Heart Outcomes Prevention Evaluation Study that in highrisk patients (vascular disease or diabetes plus one other risk factor) Ramipril compared with Placebo provides a *relative risk reduction* in myocardial infarction, stroke and death from cardiovascular causes of *21 percent* and *ARR of 3.8 percent* [36] over the mean follow up period of 5 years. There was also a *reduction in all cause death with an ARR of 1.8 percent* [36].

Concurrently, there was the advent and evolution of percutaneous approaches to revascula‐ rization. The first generation of angioplasty that truly adopted popular practice involved serial balloon inflations at the site of stenoses restore normal flow dynamics down the conducting epicardial vessels [6]. This approach, although promising was limited by a high rate of restenoses as a result of localized vascular recoil and epithelial hyperplasia [20, 37]. The bare metal stents (BMS) were created as a scaffolding technique that limited the degree of recoil but still faced significant re-stenosis rates due to mediated by injury to the medial layer, increased inflammation resulting from stent strut penetration into the lipid core and ultimately neoin‐ timal growth [38].

Pacitaxel and Sirolimus DES were developed in the next phase to overcome the challenge of restenosis requiring repeat intervention [20]. Although there was no difference in mortality or rates of myocardial infarction seen with DES compared with BMS, there were considerable reductions in restenosis rates with an estimated RRR of 0.44 [21, 22, 39-41].

Early enthusiasm for the use of drug eluting stents was curbed by a significantly higher rate of stent thrombosis, particularly in the face of an initially shorter duration (6 months) of dual antiplatelet therapy (DAPT) [22, 42, 43]. Currently the American College of Cardiology/ American Heart Association (ACC/AHA) recommends at least *12 months of DAPT* in patients receiving DES for non-ACS indication and *12 months of DAPT* for ACS indication regardless of the stent type (BMS or DES) *(Class I recommendation, Level B evidence)* [14].

The most recent development in stent technology has been the introduction of secondgeneration (everolimus and zotarolimus) drug eluting stents. A large Swedish registry observational study containing 94, 384 patients demonstrated the advantage of the secondgeneration stents over its predecessors (first generation DES and BMS) both in terms of *restenosis* and *definite stent thrombosis* [44]. The second generation DES in this study was shown to have lower risk of restenosis compared with both BMS and the first generation DES with **Hazard Ratios (HR**) of **[0.29, 95% confidence interval (CI) 0.25-0.33]** and **[0.62, CI: 0.53 -0.72]** respectively [44]. The Cobalt Chromium Everolimus eluting stents (CoCr EES) have shown the most promise in reducing stent thrombosis. In a recent network meta-analysis of 50844 patients, the CoCr EES was shown to have a lower rate of 1 year definite stent thrombosis compared to both paclitaxel DES and sirolimus DES with odds ratio (OR) of **[0.41 95% CI 0.24-0.70]** and **[0.28 95% CI 0.16-0.48]** respectively [24]. The CoCr EES also had a lower rate of definite stent thrombosis compared with BMS at 1 year and 2 years with an odds ratio [OR] of [**0.23 95% CI 0.13-0.41) and [0.35, 95% CI 0.17-0.69]** respectively [24]. Finally, compared to even the zotarolimus second generation DES, the CoCr EES still demonstrated a robust reduction in stent thrombosis with an OR **[0.21, 95% CI 0.17-0.69]** at one year [24].
