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The SYNTAX trial which 1800 patients with left main (LM) or three-vessel coronary artery disease were randomly assigned to undergo coronary artery bypass graft (CABG) or PCI with TAXUS drug-eluting stent to determine which was the better revascularisation strategy, included patients with a lesion complexity (3 vessels diseased and/or left main stenosis) that had not been included in prior studies. The primary clinical endpoint was a composite of major adverse cardiac and cerebrovascular events (MACCE) (i.e., death from any cause, stroke, myocardial infarction (MI), or repeat revascularisation) throughout the 12-month period after randomisation. In addition, the 12-month rates of MACCE were analysed on the basis of the SYNTAX score and compared with the use of a chi-square test. The SYNTAX score reflects a comprehensive anatomical assessment, with higher scores indicating more complex coronary disease; a low score was defined as ≤22, an intermediate score as 23 to 32, and a high score as ≥33.

• In an analysis of secondary endpoints, the two treatment groups had similar rates of death from any cause, stroke, or MI (7.6% for PCI and 7.7% for CABG). Patients undergoing PCI were more likely than those undergoing CABG to require repeat revascularisation (13.5% vs. 5.9% respectively) but were less likely to have a stroke (0.6% vs. 2.2% respectively).
• The angiographic-based SYNTAX Score (www.syntaxscore.com) is an innovative tool to describe coronary vasculature complexity (technical and anatomical), and predict outcomes. This semi-quantitative, visual score helps interventional cardiologists and surgeons to be aware of the anatomical complexity and anticipate procedural difficulties and outcomes. The SYNTAX Score will be updated and adjusted based on the 1-year clinical outcomes and probably revised to optimise its prognostic value. In the future more data will be collected to be able to stratify individual patients according to different variables.
• The raw SYNTAX Score is a good predictor of MACCE but does not account for comorbidity or health history.

Increasing SYNTAX Scores (and lesion complexity) are related to increased adverse outcomes in PCI, whereas outcomes of CABG are independent of SYNTAX Score. Among patients in the PCI group with high SYNTAX scores (≥ 33), not only was the overall rate of MACCE significantly increased, but also the rate of the composite components of death, stroke, and MI (11.9% vs. 7.6% respectively in the PCI and CABG groups). This finding suggests that a percutaneous approach should be avoided in patients with high SYNTAX scores.
Patients with a high SYNTAX Score need an “individualised” approach, especially in the presence of diabetes and/or with bifurcation lesions.

• CABG remains the gold standard of care for patients with three-vessel or LM coronary artery disease, since the use of CABG, as compared with PCI, resulted in lower rates of the combined endpoint of MACCE at 1 year.
• Based on a non-significant difference in MACCE at 1 year, the SYNTAX results suggest that 66% of all patients with threevessel or LM coronary artery disease are still best treated with CABG. For the remaining 1/3 of such patients with a low SYNTAX Score (0-22), PCI may be considered as an alternative to surgery (with the exception of insulino-dependent diabetic patients). Again it should be remembered that this statement is based on 1 year data. Longer follow-up results will be presented during the ESC meeting. According to previous studies one can foresee further diverge of MACCE with longer follow-up.
• A Heart Team Concept is mandatory for such patients with MVD or LM stenosis. In complex patients, the diagnostic procedure should be separate from the PCI, when eventually indicated. Time is needed in order to discuss management options, allowing for an informed decision.

The objective of FAME study was to demonstrate that Fractional Flow Reserve (FFR) – guided PCI in patients with MVD is superior to current angiography-guided. PCI. It is a randomised multicenter study, including 1005 patients undergoing DES-stenting for MVD in 20 US and European centers. The FAME study was designed to reflect daily practice in performing PCI in patients with MVD, thus, the inclusion criteria were all patients with MVD (at least 2 stenoses ≥ 50% in 2 or 3 major epicardial coronary arteries) amenable for stenting, including patients with previous MI, acute coronary syndrome (ACS), poor left ventricular function, previous PCI, diabetes, proximal left anterior descending (LAD) and chronic total occlusion (CTO). Exclusion criteria were patients with LM disease, previous bypass surgery, acute ST-segment Element Myocardial Infacrtion (STEMI) or extremely tortuous or calcified coronary arteries.
The primary endpoint was the composite of death, MI, or repeat revascularisation (MACE) at 1 year. The secondary endpoints were the individual components of MACE at 1 year, functional class, the use of anti-anginal drugs, health-related quality of life (EuroQOL-5D), procedure time, amount of contrast agent used during procedure and the cost of the procedure. PCI was performed according to local routine. Only DES were used. FFR was measured by Pressure Wire (Certus wire, RADI Medical Systems) with hyperemia induced by i.v. adenosine (140 µg/kg/min) in femoral vein. Follow-up at 1 month, 6 months, 1 year were reported and Plavix (clopidogrel) was recommended in allpatients for 1 year. Following the randomisation, the Angio-guided and FFR-guided groups included 496 and 509 patients, respectively. There is satisfactory statistical power for superiority.
In the FFR group, 37% of patients had a FFR< 0.80 (threshold for non-ischemic lesions). The primary endpoint rate at 1 year was 18.4% in the angio group and and 13.2% in the FFR group (p=0.02). The absolute difference in MACE-free survival at 1 year was 5.3%.
In analysing the primary and secondary endpoints, the conclusions of the FAME trial can be summarised as follows:

• The routine measurement of FFR during PCI with DES in patients with MVD:
  • is superior to current angiography-guided treatment strategy, in reducing by ~30% the rate of the composite endpoint of death, MI, re-PCI and CABG, at 1 year. This strategy also reduces individual endpoints such as mortality and MI at 1 year.
  • is cost-saving, greatly reducing the number of stents used
  • does not prolong the procedure
  • reduces the number of stents used
  • decreases the amount of contrast agent used and results in a similar, if not better, functional status
• FAME trial supports the evolving paradigm of “Functionally Complete Revascularisation”, i.e. stenting of ischemic lesions and medical treatment of non-ischemic ones..
• FFR confirms to be a very helpful instrument for more accurate decision making during interventional procedures

What did we learn from the Glimpse into the Future session on Coronary Revascularisation?

• There are limitations to be considered for proper interpretation of trial results when analysing subsets that are different from the predefined primary endpoints.
• Decisions on where to place the bar for significance of non-inferiority when comparing two options is certainly crucial, and somewhat arbitrary. However, consensus on this matter had been reached prior to trial onsent. Questioning post-hoc the initial decisions taken by the panel of experts at the time of trial design is unfair…
• The Heart Team approach seems more necessary than ever
• FFR proved to be a very helpful instrument for more accurate decision making during interventional procedures and to some extent recognition of complications like small dissections. Perhaps IVUS and OCT will also have a significant role in the future.
• The SYNTAX Score represents a great tool for a better analysis of the angiogram, helps the interventional cardiologist in his decision making and prognostication but also, the SYNTAX Score will be useful indirectly to the heart surgeon when deciding for a surgical option. Using the same score in order to keep track of indications with either PCI or CABG will be helpful during later follow-up.
• Diabetic patients with MVD or LM stenosis still require much more repeat revascularisation with PCI; therefore, surgery is to be recommended in most cases. Z No doubt bifurcations and trifurcations remain a challenging subset. Results by PCI are improving but again, post-procedural MACE favors surgery in many patients.
• Will the post-SYNTAX era provide even better results? Are we “entitled” to use other DES instead of TAXUS? While awaiting future trial results, practice should be based on evidence, and for the time being, SYNTAX sets the benchmark for MVD revascularisation.
• All these trials bring us very relevant information, but we have to integrate this information and act as DOCTORS and not only as technicians, however expert in percutaneous interventions we may be. We have to indicate PCI for those who have a low SYNTAX Score (specially with high EuroScore) and we have to indicate surgery as the best option to those who have a high SYNTAX Score. Otherwise, a consensus has to be reached within the HEART TEAM forum. Today, two out of every 3 patients with MVD or LM stenosis will be better treated by surgery.

Diabetic patients are increasing in number, many patients with pre-diabetes are not identified, while they may respond differently to revascularisation procedures. The Euro Heart Survey revealed a diabetes prevalence of 31% in patients with coronary artery disease (CAD). This figure increases to a remarkable 46% when those without known diabetes were tested and a further 25% were found to have newly diagnosed impaired glucose tolerance (IGT). Type 2 Diabetes mellitus (DM) and pre-DM are frequently unknown at the time of CAD diagnosis. Thus, all patients with CAD should be screened for diabetes, preferably with the oral glucose tolerance test (OGTT) (ESC recommendation class IB)
Insulin resistance is associated with smooth muscle proliferation, excessive matrix deposition, endothelial dysfunction, and delayed wound healing; the result is an abnormal response to vascular injury. The clinical consequences are greater plaque burden, diffuse long lesions and small vessel disease.
Randomised clinical trials involving revascularisation in diabetics are limited to subgroup analysis, with small numbers, leaving currently available studies underpowered for appropriate statistical conclusion. Diabetes remains a problem for both revascularisation options: an increased rate of need for repeat revascularisation after PCI with stent and an increased rate of 5 year mortality after CABG, as compared with non-diabetic patients.
Following a review of existing data, diabetic patients with MVD and/or LM disease should be considered by a multidisciplinary team before a strategy is proposed for coronary revascularisation. All such patients should be risk stratified according to their SYNTAX Score and EuroSCORE. Other risk factors, such as left ventricular function also play an important role in decision making. PCI may be considered as an appropriate alternative to CABG in patients with low SYNTAX Scores while CABG using total arterial revascularisation should be preferred in patients with high SYNTAX and low EuroSCORE.
Type 2 diabetes mellitus impacts on therapeutic strategies during and after PCI. Careful attention should be given to optimal antiplatelet treatment including anti GpIIb/IIIa in patients presenting ACS, in addition to clopidogrel and aspirin. Early results suggest a possible benefit of Prasugrel in reducing the incidence of MACE and/or stent thrombosis in diabetic patients presenting with ACS and undergoing PCI. In the TRITON TIMI 38 trial, the rate of MACE in the subgroup of patients treated with Prasugrel is significantly lower when compared with patients treated with Clopidogrel (12.2% and 17.0% respectively, p< 0.001) and the rate of stent thrombosis was significantly higher in the group of patients treated with Clopidogrel as compared with Prasugrel (3.6% and 2.0% respectively, p=0. 007) (Wiviott et al. Circulation, 2008).
After revascularisation, the use of evidencebased multifactorial pharmacotherapy is essential in adding betablockers, statins and ACE inhibitors and clear targets should be acheived: low-density Lipoprotein (LDL) < 0.80 g/l, blood pressure < 130/75 mmHg, glycaemia control, weight control and lifestyle counselling.
The use of DES, as compared with BMS, decreased the need for clinically-driven repeat target vessel revascularisation. However, the potential risk for stent thrombosis should be seriously taken into consideration in diabetic patients. In randomised clinical trials, overall mortality and MI rates are similar in DES and BMS groups at long-term follow-up.
Meta-analysis of randomised trials or registries comparing Sirolimus or Placitaxel eluting stents (SES or PES) did not demonstrate a significant difference in clinical outcomes between the two stents (Mahmud et al. J Am Coll Cardiol, 2008).
The overall mortality and MI rate is lower in the DES group as compared with the BMS group of diabetic patients included in the Massachusetts Data Analysis Center Registry (Garg et al. Circulation, 2008).
In the subgroup analysis of diabetic patients included in the SCAAR registry, the rate of clinical restenosis was higher for patients receiving Endeavor stent as compared with patients receiving SES or PES.

The objective of primary percutaneous coronary intervention (PPCI) in patients with STEMI is to restore the coronary flow and myocardial tissue reperfusion in order to improve clinical outcomes. To reach these objectives requires a better understanding of the complexity of the problem. Factors contributing to better outcomes are shorter total ischemic time, mechanical thrombus aspiration and proper use and choice of stents in order to ensure culprit vessel patency in the long-term.
Time is muscle . . . we must translate that into practice. Ideally, PPCI (balloon inflation) should be performed as soon as possible and no later than 2 hours after the first medical contact.
It is critical for PCI-capable hospitals to implement protocols and critical care pathways to achieve a door to balloon time < 90 min on all eligible STEMI patients.
In community hospitals that are not PCIcapable, it is equally important to implement protocols and critical care pathways to choose a reperfusion approach, fibrinolysis or PPCI rapidly and to immediately transfer the patient to a PCI-capable hospital for either rescue PCI after failed fibrinolysis or a pharmaco- invasive approach after successful fibrinolysis. Future strategies should focus on decreasing total ischemic time beyond what may be achievable by improving in hospital and between hospital time delays.
Strategies to shorten total ischemic time include an earlier diagnosis utilising a prehospital electrocardiogram and developing systems and networks for ambulance triage that will eventually bypass community hospitals which do not have PCI capability. Likewise, it is recommended to bypass the emergency department in PCI capable hospitals and to transport the "definite STEMI" patient directly to the catheterisation laboratory. These are complex issues with major regional and national differences in the manner in which they will be addressed. This approach requires collaboration and integration across a continuum from emergency medical services, emergency departments in a geographic region, and cardiac catheterisation laboratories.
This strategy must be sensitive to critical care access hospitals in rural communities as well as competitive scenarios between urban PCI capable hospitals, with the overriding goal being the most expedient care for the STEMI patient. The triage or transport of every chest pain, unstable angina, or non- STEMI patient immediately to a cardiac catheterisation laboratory is neither realistic nor desirable.
Optimal treatment of STEMI should be based on the implementation of an emergency medical system (EMS) supervising a network between hospitals with various levels of technology, connected by an efficient ambulance (or helicopter) service. The main features of such a network are a clear definition of geographical areas of interest, shared protocols based on risk stratification, and transportation with appropriately equipped and staffed ambulances (or helicopters). This requires persuading stakeholders outside the clinical community, particularly the public, paramedics and politicians of the need for transportation infrastructure and protocols which reliably support the transfer of patients to a PPCI unit no later than 2 hours after the first medical contact. Synergetic cooperation between paramedics and local hospitals, optimising travel times and minimising the number of doors are mandatory. In-hospital protocols should point out the importance of avoiding unnecessary gatekeeping doors and doctors before installing the patient in the cathlab. A continuing assessment of processes and performances should be promoted within each hospital in order to focus efforts on possible improvements.

When PPCI is performed, optimal antiplatelet and antithrombotic therapy in combination with manual aspiration thrombectomy seems crucial to improve myocardial reperfusion and clinical outcomes.
A meta-analysis of 8 randomised clinical trials (RCT) including 3.949 patients seems to demonstrate that Abciximab in PPCI provides an early and sustained clinical benefit in decreasing the rate of death and re-MI without a significant difference in major bleedings. Despite the negative results of the FINESSE trial, there is evidence of beneficial effects of the early administration of Gp IIb–IIIa inhibitors. This should still be considered a reasonable strategy, especially in highrisk patients and within the first hours (< 2hours) from symptom onset. This is in accordance with ACC/ AHA STEMI guidelines that suggest Abciximab administration as early as possible (class IIa).
It remains to be elucidated whether Abciximab provides an additional benefit to STEMI patients who receive an optimal clopidogrel treatment prior to PCI. Data from the BRAVE-3 trial have shown no benefit in infarct size and 30-day mortality when a clopidogrel loading dose of 600 mg was administrated. Keeping in mind the relationship between the risk profile and mortality benefit from Abciximab administration, the lack of effect may be anticipated since the mortality rate in BRAVE-3 was lower than 3%. In the On-TIME 2 trial (n 984) pre-hospital (in ambulance or referral center) initiation of high-bolus dose Tirofiban (Bolus: 25 µg/kg & 0.15 µg/kg/min infusion) in association with aspirin, clopidogrel (600 mg), and heparin improved ST resolution but was not associated with more patency of the infarct vessel. Mortality at 30 days or 1 year was not reduced in the group of patients treated with PCI receiving Tirofiban when compared with placebo.
Bivalirudin, a direct thrombin inhibitor, has been investigated as an adjunct antithrombotic therapy in patients undergoing PCI. In the Harmonising Outcomes With Revascularisation and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial, 3.602 patients undergoing PCI were randomly assigned in an unblinded fashion to receive either Bivalirudin with provisional use of GPIIb/IIIa inhibitor or heparin (or enoxaparin) plus a GPIIb/IIIa inhibitor. The primary endpoint (composite of 30-day incidence of MACE or major bleeding), was significantly reduced by Bivalirudin due to a significant reduction in major bleeding. Allcause mortality at 30 days was 1% lower, but acute stent thrombosis occurred more frequently (1.3% vs 0.3%). Bivalirudin is given as an i.v. bolus of 0.75 mg/kg followed by an infusion of 1.75 mg/kg/h not titrated to ACT and usually terminated at the end of the procedure.
Thus, a very early administration of Abciximab or Tirofiban in high-risk patients or as an alternative, the use of Bivalirudin on the table (with bailout Abciximab depending on the angiography) in patients undergoing primary PCI for STEMI can be considered.
Levels of recommendation and evidence for the various antiplatelet and antithrombotic drugs are shown below, from the recent update in ESC Guidelines on the treatment of STEMI.

Several randomised clinical trials (Typhoon, HORIZONS-AMI), with medium-term followup, have shown that DES (Typhoon trial comparing the CYPHER stent with BMS, and HORIZONS-AMI comparing the TAXUS stent with other BMS) reduce the risk of reintervention compared with BMS, without having a significant impact on the risk of stent thrombosis, recurrent MI, and death.
It should be remembered however that these trials included highly selected patients. For instance, Typhoon trial included 35% of screened STEMI population only.
C. Spaulding presented the 4 year follow-up of the Typhoon trial. The initial reduction in the primary endpoint of target vessel failure (TVF) was supported by an ongoing significant reduction in TLR at 4 years (9.6% vs 17.2 % respectively for DES and BMS). There were no differences in the key safety parameters at 4 years. No data regarding new generation DES in terms of safety and efficacy are available in this patient subset (only SES and PES have been specifically tested in AMI patients). A number of clinical registries have been reported. These studies represent real world population, but their results may be subject to clinical bias and under-reporting of events.
When to use DES in PPCI? Good selection of candidates is mandatory in such scenario. I would implant a DES during primary PCI if: the patient has a good chance of surviving a heart attack, he will be compliant to prescribed dual-antiplatelet regimen, and the target lesion presents a high risk for restenosis, if it was treated by bare metal stent

30-50% of patients with STEMI have MVD and 60-90% of patients with cardiogenic shock have multivessel or LM disease. PPCI during evolving acute STEMI should be restricted to culprit vessel only. Immediate non-culprit vessel PCI is a reasonable strategy in patients with cardiogenic shock or hemodynamic compromise.
In such clinical situations, the use of ventricular assist devices can improve outcomes of patients with poor LV function.
Acute hemodynamic deterioration may have several reasons and may not always require acute multivessel PCI.

A staged revascularisation procedure is recommended for stable STEMI patients after successful PPCI:

• Benefit of optimal medical plaque stabilisation may be unpredictable in the early post-infarction phase
• The best timing for non-culprit vessel revascularisation after STEMI in patients with MVD should be defined by the HEART TEAM, including cardiologists, interventional cardiologists and cardiac surgeons according to a judgment based on the clinical condition and objective signs of ischemia.
• Revascularisation before discharge is acceptable only if the patient suffers from recurrent ischemia. For the other patients, the best timing depends on each particular clinical and angiographic situation: after 3 weeks, 3 months, or 6 months, all these options can be considered. Guidelines recommend to target additional revascularisation procedures to hemodynamically significant lesions, such that revascularisation is ischemia-driven.
• As to indications for CABG, a consensus should be reached by the HEART TEAM and the same criteria applied as in non-STEMI patients: 2/3 of all patients with MVD or LM stenosis today will be better treated by surgery. Surgery will likely be the option of choice in MVD with total occlusions, LM involvement, complex bifurcations or very long lesions

Surgical aortic valve replacement (AVR) remains the gold standard treatment for eligible patients with severe aortic stenosis (AoS) following a global evaluation by a Heart Team that should include a cardiac surgeon, cardiologist and anaesthetist.

1. TAVI may be considered as an alternative therapeutic option for patients with severe symptomatic AoS in the presence of a formal contraindication to surgery or other characteristics that would limit their surgical candidacy because of excessive mortality (determined by the Heart Team).
2. The decision to propose TAVI must be based on a discussion and consensus between all members of the Heart Team, taking into account the potential for functional improvement and a decent life expectancy (possible responders).
3. Currently, the balloon expendable Edwards SAPIEN (Edwards Lifescience, Irvine, California) and the self-expandable CoreValve ReValving System (CoreValve Inc., Irvine, California), have obtained the CE mark and have been implanted worldwide during pilot, feasibility or post-market studies and registries. Other transcatheter aortic valve systems are under investigation or undergoing first-in-man implantations.
4. The Edwards SAPIEN valve can be implanted using either the transfemoral or the transapical approaches (Ascendra Transapical Delivery System, Edwards Lifescience); the CoreValve Revalving system is implanted via the transfemoral route; the subclavian or axillary route has been used with the CoreValve Revalving system in a limited number of patients.
5. Observational registries have confirmed the feasibility of TAVI with an implantation success rate of around 95% and excellent immediate haemodynamic results.
6. Peri-procedural related complications, including vascular access complications, permanent atrio-ventricular block requiring pacemaker implantation, stroke, valve migration and paravalvular insufficiency require more thorough investigation and future prevention.
7. The data derived from observational registries show a mortality rate at one month at around 10-15% and a one-year survival rate at around 75%, with 60-70% of patients free of any complication. The rate of MACCE after a longer follow-up period remains unknown, as does the long-term durability of the devices. So far, there is no direct comparative clinical and cost-effectiveness data with conventional AVR or medical treatment.
8. A step-by-step, monitored training process of the entire team (including interventional cardiologist, anaesthetist, cardiac surgeon, echocardiographer and technicians) as well as close proctoring in the early phase of experience, and a monitored post-market surveillance are strongly advised. Today, uncontrolled dissemination of the procedure should be avoided.
9. TAVI procedures should be performed by a complete team (interventional cardiologist, anaesthetist, echocardiographer, technicians) in an appropriate sterile environment, with a cardiac surgery team onsite and a vascular surgeon on standby.

by Marco Roffi & Alberto Cremonesi
Great attention was also given to carotid artery revascularisation this year.. The central role of an independent neurologic assessment pre- and post-procedure for patients undergoing both carotid artery stenting (CAS) and carotid endarterectomy (CEA) was underscored. It was remembered that patients presenting with a transient ischemic attack (TIA) or minor stroke of carotid origin have a high risk of recurrence in the days and weeks following presentation.
Therefore, these patients should be immediately treated with antiplatelet agents and statins and a carotid revascularisation should be performed in the two weeks following symptom onset. The risk of a major stroke is particularly elevated in patients with recurrent/ incessant ischemic events. Those individuals need multidisciplinary care and urgent carotid revascularisation. Importantly, although symptomatic patients have a higher risk of complications at the time of both CEA and CAS compared to asymptomatic individuals, they derive a greater benefit from revascularisation. In asymptomatic patients, an estimation of the individual risk and benefit of revascularisation is critical.
With respect to the choice of the revascularisation strategy (CEA or CAS), current randomised evidence support CEA for symptomatic patients, while data in asymptomatic patients is limited. However, most of the randomised trials have been criticised for the limited endovascular experience required to enrol patients, for the possibility of performing CAS under tutoring conditions, and for the lack of mandatory use of emboli protection devices. Opposing the randomised results, the data derived from several highvolume centers and high-quality large-scale registries - with independent neurologic assessment and clinical event committee adjudication - have shown that in experienced hands CAS may deliver outcomes complying with current CEA guidelines, namely a death or stroke rate of < 3% and <6% for asymptomatic and symptomatic individuals, respectively.
Based on current evidence, CEA should be considered the therapy of choice for symptomatic patients while CAS should be considered for patients at high risk for surgery. Importantly, the decision process should be multidisciplinary and should be based on the surgical risk of the patient, the anatomy of the aortic arch and supra-aortic vessels, and the expertise that is available locally.

Next chapter online in October 2009. Connect to www.pcronline.com