The adequacy of myocardial revascularization in patients with multivessel coronary artery disease

IJCA-16330; No of Pages 10 International Journal of Cardiology xxx (2013) xxx–xxx

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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard

Review

The adequacy of myocardial revascularization in patients with multivessel coronary artery disease Marco Zimarino a,⁎, Nick Curzen b, Vincenzo Cicchitti a, Raffaele De Caterina a a b

Institute of Cardiology and Center of Excellence on Aging “G. d’Annunzio” University of Chieti, Italy University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom

a r t i c l e

i n f o

Article history: Received 28 June 2012 Received in revised form 4 April 2013 Accepted 3 May 2013 Available online xxxx Keywords: Multivessel coronary artery disease Percutaneous coronary intervention Coronary artery bypass grafting

a b s t r a c t In patients with multi-vessel coronary artery disease (MVCAD) myocardial revascularization may be accomplished either on all diseased lesions – complete myocardial revascularization – or on selectively targeted coronary segments by percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). Complete revascularization has a potential long-term prognostic benefit, but is more complex and may increase in-hospital events when compared with incomplete revascularization. No conclusive agreement has been yet reached on the “optimal” extent of revascularization, and guidelines have only recently mentioned the adequacy of revascularization in the decision whether to submit a patient to CABG or PCI. In the absence of any trial specifically designed to assess the relative benefit of either strategy, the present review explores current concepts about the completeness of revascularization, the growing evidence on the relevance of lesion and myocardial functional evaluation, and analyzes currently available data in relation to different clinical settings, including acute coronary syndromes, diabetes, chronic kidney disease and impaired left ventricular function. Considerations on the adequacy of revascularization should guide the choice among PCI and CABG in patients with MVCAD during the decision-making process, taking into account the clinical presentation, the extent and relevance of ischemia and the presence of other comorbidities. © 2013 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Multi-vessel coronary artery disease (MVCAD) – traditionally defined as the presence of a ≥50% diameter stenosis (DS) in more than an epicardial vessel at angiography – is documented in 40–60% of patients undergoing coronary angiography, and – depending on the clinical presentation – has an adverse prognostic implication on outcome as compared to single vessel disease. The “optimal” extent of myocardial revascularization in patients with MVCAD is controversial and there is no universal consensus. Guidelines have only recently started to consider the adequacy of revascularization among the issues to take into account in the decision as to whether to submit a patient to coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) [1–3]. There is lack of trials specifically designed to directly compare complete vs incomplete revascularization, and guidelines have only recently mentioned the adequacy of revascularization in the decision of whether to submit a patient to CABG or PCI [4]. Any evidence on the adequacy of revascularization can be therefore derived from registries or trials otherwise designed.

⁎ Corresponding author at: Institute of Cardiology, “G. d'Annunzio” University of Chieti, C/o Ospedale SS. Annunziata, Via dei Vestini, 66013 Chieti, Italy. Tel.: +39 0871 358622; fax: +39 0871 402817. E-mail address: [email protected] (M. Zimarino).

We will therefore summarize existing data in relation to the extent of revascularization by CABG and PCI in MVCAD and try to identify – based upon available literature – the “optimal” evidence-based strategy in different clinical scenarios. 2. Methods We reviewed papers published in English in the period 1990–2012 on the adequacy of myocardial revascularization in MVCAD patients using the PubMed database. We used the keywords “coronary”, “*complete*” and “revasculari*” or “multiv*”. References of the articles identified in this manner also searched to locate additional references that – non-identified by the initial search strategy – might be useful for the purpose. Clinical studies and meta-analyses were included, abstracts and case reports were excluded; and discordance regarding inclusion was resolved by discussion. 3. The body of proof The issue on the adequacy of myocardial revascularization in patients with MVCAD has only recently regained interest from the scientific community. Guidelines of the European Society of Cardiology (ESC) on myocardial revascularization first mentioned the adequacy of revascularization in 2010 among the items to be considered in the

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Please cite this article as: Zimarino M, et al, The adequacy of myocardial revascularization in patients with multivessel coronary artery disease, Int J Cardiol (2013), http://dx.doi.org/10.1016/j.ijcard.2013.05.004

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choice among PCI and CABG [4], subsequently listed among the factors that should guide the strategy of revascularization in the 2011 guidelines on PCI edited from the American College of Cardiology (ACC), American Heart Association (AHA) and Society for Cardiac Angiography and Interventions (SCAI) [3]. The ESC guidelines sparsely highlight the benefits of complete revascularization, mentioning that complete surgical revascularization is recommended in patients with reasonable life expectancy, incomplete revascularization by PCI is associated with a higher 3-year mortality and may be harmful in patients with complex MVCAD [4]. The ACC/AHA/SCAI document dismisses the topic of revascularization completeness citing only outdated manuscripts (from 1983 to 1998) and commenting that complete revascularization by CABG seems to influence long-term prognosis positively, while for PCI the influence of the extent of revascularization on outcome is less clear [3]. One of the limitations in making educated decisions among different options is the absence of an up-to-date comprehensive definition of the adequacy of myocardial revascularization itself. Provided the absence of a universally accepted definition of the extent of revascularization, “complete revascularization” was variously classified in different trials and therefore comparison of the results deriving from different studies must be interpreted with caution [5–7]. The long-term benefits of complete anatomical myocardial revascularization – all stenotic vessels revascularized, irrespective of size and territory supplied – became a tenet after the reports from the Coronary Artery Surgery Study (CASS) were available [8]. The treatment of the lesion responsible (“culprit”) of an acute coronary syndrome (ACS) or of the most severe stenosis in a stable CAD is defined “incomplete revascularization”, a strategy that is associated with reduced periprocedural adverse events [9]. The presence of significant comorbidities and of complex anatomic features strongly influence the decision regarding the extent of revascularization [6,7]. Incomplete revascularization is a surrogate marker of comorbidity (patient frailty, absence of myocardial viability and/or ischemia, and presence of mitral regurgitation) and of anatomical coronary complexity (total vessel atherosclerotic burden, small vessels, lesion tortuosity and calcification, presence of bifurcations and chronic total occlusions). Differences in baseline variables of patients enrolled in both trials and registries appear to play a major confounding role, as data may be biased in favor of complete revascularization by selecting the healthier subject for complete rather than incomplete revascularization [6]. Besides this, multivariate and propensity score analysis has been used to account for differences in baseline characteristics, but no statistical analysis can completely adjust all confounding variables. Eventually, a shorter-term follow-up may advantage the reduced risk of adverse periprocedural events pursued with an incomplete revascularization, while a longer-term follow-up might highlight the benefits deriving from a more extensive treatment. Among 13,016 patients with MVCAD who underwent bare metal stent (BMS)-PCI identified in the New York State's PCI Reporting System during the years 1999–2000, complete revascularization was achieved in 29.2% of cases and – when compared with pair-matched subjects who received incomplete revascularization – was associated with a relative 12% increase in 8-year survival (P = 0.04) [10]. Even larger benefits were documented among patients receiving a complete as compared with an incomplete revascularization with drug-eluting stent (DES)-PCI, where the documented reduction of mid-term relative risk for death or myocardial infarction (MI) ranged from 30 to 60% [11,12]. Such studies were selected in a recent meta-analysis [13] where a total of 37,116 MVCAD patients undergoing PCI were included: compared to incomplete revascularization, patients undergoing complete revascularization had significantly lower risk of mortality (relative risk (RR) 0.82; P = 0.05), non-fatal MI (RR 0.67; P b 0.01) and subsequent CABG (RR 0.70; P = 0.02) whereas no difference was noted in the incidence of repeat PCI. Aside from large-scale registries and meta-analyses, randomized clinical trials comparing long-term outcomes of PCI vs. CABG – although

not specifically directed to compare complete vs. incomplete revascularization – represent a valuable source of data for post-hoc analyses. The benefit deriving from a complete revascularization seems notably more evident after PCI than CABG: in the Arterial Revascularization Therapies Study (ARTS), patients with incomplete percutaneous revascularization showed a significantly lower event-free survival (69%) than patients receiving complete revascularization with stent-PCI (77%; P b 0.05); conversely, at one year, CABG patients with incomplete revascularization showed only a marginally lower event-free survival rate than those with complete revascularization (88% vs 90%) [14]. Similarly, in the evaluation of the Bypass Angioplasty Revascularization Investigation (BARI) [15] surgical results, the construction of >1 graft to any system other than the left anterior descending (LAD) did not confer any long-term advantage, and was even deleterious; 7-year death or MI was highest (33%) when >1 anastomosis was constructed to any nonLAD system (relative risk 1.37, P b 0.05) [16]. Moreover, among 8806 patients with 3,5 years follow-up, in the presence of a left internal mammary artery to left anterior descending artery bypass, incomplete revascularization of the circumflex or right coronary artery territory did not affect early nor long-term survival [17]. Presumably, a higher percentage of complete revascularization in CABG patients may dilute the clinical implication of complete revascularization. In recent subgroup analyses of the SYNergy between percutaneous coronary intervention with TAXus and cardiac surgery (SYNTAX) trial, complete revascularization was achieved more easily with CABG than with PCI [18]. Presence of a chronic total occlusion was the strongest independent predictor of incomplete revascularization after PCI [18], and incomplete revascularization was identified as an independent predictor of adverse events in PCI (hazard ratio, HR = 1.55, P = 0.004) but not in CABG patients [19]. Notably, the impact of the adequacy of revascularization on longterm survival seems strongly dependent on age among patients undergoing CABG: in a propensity-score-matched analysis performed on data from 6539 consecutive patients, surgical incomplete revascularization was independently associated with higher long-term mortality only in patients b 60 years (HR = 3.27; P = 0.02), not in patients 60 to 70 years and >70 years [20]. 3.1. Functional evaluation Despite robust guidelines recommending functional evaluation of reversible myocardial ischemia prior to elective revascularization, hence emphasizing the importance of the concept that “the target of revascularization therapy is myocardial ischemia, not the epicardial coronary disease itself” [4], the majority of patients with stable coronary artery disease undergoing elective PCI have no preceding documentation of myocardial ischemia [2,21]. When the indications for >500,000 PCIs performed in >1000 US hospitals were analyzed and judged by an expert panel, almost all PCIs (99%) in ACS were classified as appropriate, while this was the case in only 50% of stable patients [22]. The lack of functional evaluation of lesion significance in terms of ischemia and viability of the dependent myocardial territory in clinical trials on revascularization strategies in stable CAD patients is a critical methodological, yet poorly controlled, factor influencing and biasing the interpretation of available data. As a proof of concept, among almost 2000 MVCAD patients undergoing either DES-PCI or CABG in the absence of any functional evaluation of reversible ischemia or lesion assessment, similar 5-year outcomes were observed for patients with complete and incomplete “angiographic” revascularization, regardless of the revascularization strategy [23]. The clinical implication of the reduction of ischemia is well documented in the Clinical Outcomes Utilizing Revascularization and AGgressive drug Evaluation (COURAGE) study [24], where PCI and optimal medical therapy (OMT) had apparently similar clinical outcomes in a large population of stable patients. This inevitably led to the widely publicized conclusion that OMT is as effective as PCI in stable coronary artery disease. Such a

Please cite this article as: Zimarino M, et al, The adequacy of myocardial revascularization in patients with multivessel coronary artery disease, Int J Cardiol (2013), http://dx.doi.org/10.1016/j.ijcard.2013.05.004

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conclusion deserves however a closer scrutiny. The nuclear imaging substudy of COURAGE, although not powered to detect differences in clinical outcomes according to treatment allocation, provided insight into the importance of the functional evaluation of the presence and, in particular, the extent of ischemia [25]. Patients experiencing a ≥5% reduction in the ischemic burden here featured an 87% 1-year event-free survival, significantly higher than in subjects without ischemia reduction (75%, P b 0.05). The availability and extensive validation of the fractional flow reserve (FFR) now offer a surrogate for ischemia and thereby represent an alternative to non-invasive stress imaging. The FFR is independent of heart rate, blood pressure and left ventricular contractility, and takes into account the contribution of collateral flow to myocardial perfusion [26]. An FFR value b 0.75 confirms that the stenosis has the potential to induce myocardial ischemia [27], and this has revolutionized modern interventional practice. In the Fractional Flow Reserve Versus Angiography for Multivessel Evaluation (FAME) study [28], patients who had been listed for multivessel PCI were randomized to angiographically- or FFR-guided stenting (using a cut-off FFR value of 0.80). The result was remarkable, and practice-changing: the FFR-guided strategy was not only both cost-saving and cost-effective [29], being associated with lesser use of stents (1.9 ± 1.3) and of contrast medium (272 ± 133 mL) as compared to pure angiographic guidance (2.7 ± 1.2 and 302 ± 127 mL, respectively, P b 0.001 for both), but was also associated with a significant reduction in the occurrence of the composite primary clinical end point of death, nonfatal MI and repeat revascularization at 1 year (18% vs 13%, P = 0.02) [28], as well as of mortality plus MI at 2 years (13 vs 8.4%, P = 0.02) [30]. Such emerging invasive diagnostic modality is undoubtedly going to significantly modify treatment decisions, reducing the rate of interventions in patients angiographically identified as having a MVCAD [31,32]. Similarly, there is recent evidence that surgical treatment of vessels that are not serving an ischemic myocardial territory may be disadvantageous: graft anastomosed to a functionally not relevant lesion often develop diffuse involution (the “string” sign) due to competitive flow in the native coronary artery [33], and a higher 1-year rate of occlusion has been documented for grafts anastomosed to functionally nonsignificant (21.4%) as compared to functionally significant lesions (8.9%, P b 0.05) [34]. These data have profound implications for the management of patients with MVCAD by surgery. In the decision-making algorithm of patients with MVCAD, FFR seems to perform even better than myocardial perfusion imaging (MPI) — formerly used as the FFR reference gold standard, and the ability of which to identify relative differences in perfusion between 2 myocardial territories is limited. In cases where there is significant myocardial ischemia, MPI often only identifies the myocardial perfusion defect in the most ischemic territory [35,36]. Such a characteristic of MPI may limit its clinical utility to guide revascularization in patients with MVCAD. Not surprisingly, when compared in the functional evaluation of patients with MVCAD, FFR and MPI showed a poor concordance (k per patient = 0.14, per-vessel = 0.28); MPI underestimated by

36% and overestimated by 22% the ischemic territories detected by FFR [37]. A functional evaluation of the lesion severity may now be obtained also by non-invasive coronary imaging: the Determination of Fractional Flow Reserve by Anatomic Computed Tomographic AngiOgraphy (DeFACTO) trial documented that FFR can be non-invasively obtained with computed tomography (CT) angiography and, together with CT itself, is associated with improved diagnostic accuracy and discrimination compared with CT alone for the diagnosis of hemodynamically-significant CAD [38]. Cardiac magnetic resonance (CMR) is increasingly utilized in ischemic heart disease for both (i) the detection of lesions producing ischemia – where it is extremely accurate even when compared with FFR [39] – and (ii) the identification of myocardial viability – where the transmural extent of MI assessed by late gadolinium enhancement accurately predicts left ventricular (LV) function recovery after revascularization [40]. Therefore, it has been well documented that intervening on lesions that are not producing ischemia confers a cost in terms of adverse outcome: here OMT is indeed a better alternative. What would have been the outcome of COURAGE and even of ARTS and SYNTAX if revascularization had been ischemia-driven? A partial insight into this question perhaps derives from the FFR-guided PCI plus OMT versus OMT alone in Patients with Stable Coronary Artery Disease (FAME II) trial [41], prematurely halted by the Data Safety Monitoring Board for a highly statistically significant reduction in the need for hospital readmission and urgent revascularization when FFR-guided assessment was used compared with OMT in treating patients with stable coronary artery disease. The current evidence thus suggests that our revascularization strategy in MVCAD, whether PCI or CABG, should be ischemia- and not anatomyguided, and that this should be at lesion- and myocardium- not just at patient-level.

4. Clinical perspective A comprehensive definition of the adequacy of myocardial revascularization should take into account the size of the vessel, the severity of the lesion, the ischemic burden caused by the lesion and the viability of the depending myocardial territory (Table 1). This distinction is not just theoretical, as “complete revascularization” and “functionally adequate revascularization” are not synonymous. While in patients without any previous MI, treatment of territories subjected to hemodynamically relevant lesions provides both an anatomical and functional revascularization, in the cases of documented myocardial necrosis the discrimination between anatomical and functional revascularization becomes critical, and depends on the detection of viability in the depending myocardium. The choice between complete and incomplete revascularization – regardless the strategy of intervention – should be made after a careful analysis of the risk/benefit ratio individualized for the various clinical settings.

Table 1 Revascularization strategies.

Revascularisation strategy

Definition

Complete anatomic revascularization

Treatment of all coronary segments >1.5 mm with a ≥50% DS irrespective of their ability to produce ischaemia.

Functionally adequate revascularization

Incomplete revascularization

3

Myocardial-specific

Treatment of all coronary segments >1.5 mm with a ≥50% DS supplying viable ischemic myocardium.

Lesion-specific

Treatment of all coronary segments >1.5 mm with a FFR<0.80. Inability or unsuitability to treat all coronary segments with significant disease (either ≥50% DS or FFR<0.80) supplying viable myocardium.

DS = diameter stenosis; FFR = fractional flow reserve.

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Timing of treatment after the diagnostic angiogram is another critical issue. Regardless the extent of revascularization, an “ad hoc” procedure refers to a PCI performed in the same setting of the index angiography, “staged” to a procedure performed at a distance from the first coronary angiogram (or the completion of the first treatment). Either a complete or an incomplete revascularization may be accomplished with both “ad hoc” and “staged” PCI. “Ad hoc” PCI obviously avoids the cost and inconvenience associated with a second procedure and arterial puncture. A “staged” procedure introduces a “pause” between coronary angiography (and the possible treatment of the most clinically relevant lesion) and the subsequent revascularization, allowing to “dilute” the contrast medium amount, the risk of periprocedural injury and to better assess the clinical relevance of the revascularization itself [42]. 4.1. ST-elevation myocardial infarction In ST-elevation myocardial infarction (STEMI), primary PCI directed to the infarct-related artery (IRA) is now the universally accepted treatment of choice in both European and US guidelines [3,4]. Up to 50% of patients presenting with STEMI have MVCAD, with angiographic documentation of significant stenoses affecting a non-IRA. The documentation of MVCAD during the index procedure identifies a subgroup of patients with a more than doubled risk of 30-day mortality than subjects with the IRA as the only diseased vessel. In addition, the presence of a CTO represents a further independent predictor of both early and late survival [43]. Data from the National Cardiovascular Data Registry [44] recently questioned the benefit of multivessel PCI in STEMI even in patients with shock, by showing that PCI of all the non-IRA lesions in the same setting (“ad-hoc”) was associated with a higher in-hospital mortality (36%) as compared to IRA-only primary PCI (28%, P b 0.01). These results prompted the ESC committee to become even more restrictive in the guidelines on STEMI [45], where “multivessel PCI is justified only in patients with cardiogenic shock for the treatment of multiple, truly critical (≥ 90% diameter) stenoses or highly unstable lesions (angiographic signs of possible thrombus or lesion disruption), and if there is persistent ischemia after PCI of the supposed culprit lesion” (class of recommendation IIa, level of evidence B). Similarly, ACC/AHA guidelines on STEMI [46] recommended PCI in a non-IRA at a time separate from primary PCI in patients with spontaneous symptoms of myocardial ischemia (class I) and judged it as appropriate in patients with intermediate- or high-risk findings on non-invasive testing (class IIa). Apart from the PCI of the IRA in the acute phase, the best revascularization strategy of the remaining MVCAD is not well established: the treatment of non-IRA is deemed appropriate only in a subsequent procedure, on the basis of symptoms of recurrent ischemia or after documentation of residual ischemia at non-invasive stress testing after discharge [47]. Apart from the potential overestimation of the non-IRA severity due to the heightened vascular tone [48], concern to attempt complete revascularization in a STEMI derives from (a) the prolongation of the primary PCI procedure, which will increase the volume of contrast medium used and the connected risk of contrast-induced nephropathy (CIN) [49]; (b) the inherent risk of jeopardizing viable myocardium during revascularization of non-IRA; and (c) the higher risk of stent thrombosis by operating in the highly thrombogenic milieu around the infarction. Published data in this context are however discrepant. In the only randomized study on this topic, 214 consecutive patients with STEMI undergoing PPCI were allocated into 3 groups: culprit only — incomplete revascularization with treatment of the sole IRA during PPCI, simultaneous “ad hoc” multivessel — treatment of all diseased vessels during the index procedure, or “staged” revascularization — complete revascularization with treatment of non-IRAs in an additional procedure, usually scheduled before discharge. At a mean follow-up of 2.5 years, mortality was similar in the three groups, but adverse events occurred more

frequently (50%, P b 0.05) in the culprit-only group as compared with both simultaneous (23%) and staged (20%) revascularization [50]. In the 2003–2006 New York State database, MVCAD patients admitted for STEMI without hemodynamic compromise who had undergone IRA-only PCI had a lower in-hospital mortality (0.9%) than those submitted to “ad-hoc” multivessel PCI during the index procedure (2.4%, P = 0.04); the further completion of myocardial revascularization with early (within 60 days) staged multivessel PCI was associated with a significantly lower 12-month mortality (1.3%) when compared with a strategy of incomplete revascularization with IRA-only PCI (3.3%, P = 0.04) [51]. The recently available analysis of the Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial [52] supports the aforementioned guidelines that, compared with a staged PCI, “ad hoc” multivessel treatment during the index procedure was associated with a 4-times higher risk of 1-year mortality (9.2 vs 2.3%, P b 0.0001) and a doubled risk of stent thrombosis (5.7 vs 2.3%, P b 0.02). Further evidence in favor of a staged complete revascularization derives from a meta-analysis of 4 prospective and 14 retrospective studies involving 40,280 patients [53]; staged PCI aiming at a complete revascularization seemed the best strategy, as it was associated with lower short- and long-term mortality compared with both IRA-only PCI and single “ad hoc” multivessel PCI; “ad-hoc” multivessel PCI was associated with the highest mortality at both short- and long-term follow-up. MVCAD patients presenting with STEMI and cardiogenic shock or resuscitated cardiac arrest have an extremely high risk of adverse acute events and seem to have the most to gain from an early aggressive approach: Mylotte et al. [54] recently documented that “ad hoc” multivessel PCI – achieving a complete revascularization during the index procedure of PPCI on the IRA – was associated with a doubled 6-month survival (43.9%) as compared to IRA-only PPCI (20.4%, P = 0.0017); however, the role of a “staged” complete revascularization was not explored. In this setting, although not yet fully tested in terms of clinical effectiveness, the functional assessment of the non-IRA by means of FFR – either during the urgent coronary angiography or anyway performed during the hospitalization – might provide a valuable and safe tool for risk stratification, as it can shorten the diagnostic work-up or avoid unnecessary rehospitalization and the treatment of lesions overestimated by angiography [55]. We therefore propose to extend 2012 ACC/AHA appropriateness criteria to a functional evaluation not only related to the myocardium subtended to the non-IRA – already recommended in the 2012 appropriateness criteria for revascularization in STEMI patients [47] – but also to the myocardium subtended by nonIRA lesions (Fig. 1). Currently, 2 large trials recruiting in the UK – the Preventive Angioplasty in Myocardial Infarction Trial (PRAMI) and the Complete Versus Lesion-only Primary PCI Pilot Study (CVLPRIT) – are randomizing patients with STEMI and MVCAD to either IRA-only or complete revascularization during primary PCI. These studies may fill an important gap in our understanding of the optimal revascularization strategy in this scenario. 4.2. Non-ST Elevation Acute Coronary Syndromes In non-ST Elevation Acute Coronary Syndromes (NSTE-ACS) the identification of the “culprit” lesion can be more problematic than in STEMI, and is usually achieved by a combination of clinical factors including: (i) angiographic characteristics (high-grade lesion and the aspect of an ulcerated plaque associated with non-occlusive thrombus); and (ii) information from non-invasive diagnostic tests, such as identification of the ischemic territory by ECG (dynamic ST-T changes) and/or echocardiography (altered segmental contractility). As compared to STEMI, the thrombotic milieu and inherent procedural risks are lower in NSTE-ACS patients and therefore an “ad-hoc” complete revascularization during the index procedure can be more safely performed in

Please cite this article as: Zimarino M, et al, The adequacy of myocardial revascularization in patients with multivessel coronary artery disease, Int J Cardiol (2013), http://dx.doi.org/10.1016/j.ijcard.2013.05.004

M. Zimarino et al. / International Journal of Cardiology xxx (2013) xxx–xxx

No

Non-IRA FFR

No

“Ad hoc” PCI of all lesions with DS≥50%

Before discharge

Optimal Medical Treatment

Yes

After discharge

Recurrent symptoms or functional evaluation of residual ischemia

Anatomically Complete Revascularization

Appropriate Uncertain Inadequate

Primary PCI of IRA

STEMI in MVCAD

5

“Ad hoc” Before PCI of all discharge lesions with FFR<0.80

Yes

PCI of all lesions with DS≥50% and inducible ischemia

Incomplete Revascularization

Myocardial-specific

Lesion-specific

Functionally Complete Revascularization

Fig. 1. Appropriateness criteria for revascularization options in ST-elevation myocardial infarction. In patients with ST-segment elevation myocardial infarction (STEMI) and multivessel coronary artery disease (MVCAD), after completion of the primary percutaneous coronary intervention (PCI) of the infarct-related artery (IRA), a complete revascularization in the same urgent setting (“ad hoc”) should be discouraged. A functional evaluation of either non-IRA lesions with fractional flow reserve (FFR) or of non-IRA supplied myocardium with non invasive testing should guide a functionally complete staged revascularization. A complete anatomical revascularization – angiographically guided and without knowledge of myocardial ischemia/viability – is acceptable on non-IRA lesions with a diameter of stenosis (DS) ≥50% only with a staged procedure.

MVCAD. Nevertheless, the choice of the optimal reperfusion strategy requires careful evaluation. On the one hand, multivessel stenting is potentially associated with greater contrast load and peri-procedural MI [56], as well as with higher risk of both later restenosis and stent thrombosis. On the other hand, multivessel PCI has been repeatedly associated with lower death and MI at mid-term (18 months to 3 years) follow-up [12,57,58]. Among propensity-matched NSTE-ACS patients undergoing PCI in New York between 2007 and 2009, the 3-year mortality was similar whether the complete revascularization was accomplished during the index hospitalization or with a “staged” (within 60 days) procedure [59]. Here again, a functional assessment of lesion severity and myocardial viability is likely to be crucial to limit the intervention to coronary segments expected to provide a myocardial benefit from revascularization, thus maximizing the benefit and reducing unnecessary risks. The aforementioned FAME trial has shown that FFR “re-categorizes” patients otherwise classified as “MVCAD” by angiography, and that treatment only of lesions with an FFR b 0.80 reduces long-term adverse events related to the allegedly unnecessary deployment of stents in all lesions judged as severe only on the basis of angiography [60]. Similarly to STEMI, the timing of revascularization is also critical. Here again, complete revascularization seems to be associated with a significant benefit in terms of the reduction of mortality and MI [12,57,58]. With the purpose of obtaining a formal quantification of the extent and complexity of residual atherosclerosis after PCI, the residual SYNTAX score after PCI was calculated from 2686 patients with NSTE-ACS undergoing PCI enrolled in the prospective Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial [61]; the residual SYNTAX score was a strong and independent predictor of 1-year death and MI, having a good discriminatory power for values >8. Moreover in most studies, the definition of incomplete revascularization was based on a visual estimation of the %DS and therefore the judgment on the adequacy of revascularization was merely subjective [7]. Therefore, Rosner et al. [62] analyzed data from a systematic quantitative coronary angiography

of the entire coronary tree in 2954 patients enrolled in the ACUITY trial. Incomplete revascularization was variably defined for various DS cutoffs in vessels ≥2 mm left untreated after PCI and was associated with an increased adverse cardiac event rate using all of the DS cutoffs. A DS ≥50% showed the best discriminatory value for the definition of incomplete revascularization, as identified patients with higher 1-year rate of MI (HR = 1.58, P b 0.001) and a trend toward increased risk of death (HR = 1.43, P = 0.13). In many patients with MVCAD, CABG would be therefore the preferred treatment strategy: according to current guidelines, here PCI is not recommended in patients with baseline SYNTAX score >22 [4]. “Ad hoc” multivessel PCI, although extensively performed in low-risk patients [63], is associated with increased risk of peri-procedural damage and CIN [42]. In patients with a SYNTAX score ≤22, a staged PCI aiming to treat all significant coronary segments supplying viable myocardium after an initial PCI directed only to the culprit lesion might therefore be the strategy of choice, as it reduces the procedural risk, dilutes the amount of contrast medium over time, and also allows the functional evaluation of “presumed non-culprit” lesion-related myocardial territories, as well as patient's symptoms. Currently, there are no trial data to test this hypothesis, although the Fractional Flow Reserve versus Angiographically Guided Management to Optimise Outcomes in Unstable Coronary Syndromes (FAMOUS) study is currently recruiting in the UK. 4.3. Diabetes Diabetic patients have an accelerated disease progression and increased risk of cardiovascular events after myocardial revascularization both during hospital stay and in the long term [64,65]. The BARI trial [66] first documented that a strategy of CABG was associated with a better long-term survival compared to balloon-PCI in diabetic patients with MVCAD. In subsequent years, the relevance of this historical trial to contemporary practice has been questioned for a number of reasons including: (a) the unavailability of stents and (b) of full antiplatelet

Please cite this article as: Zimarino M, et al, The adequacy of myocardial revascularization in patients with multivessel coronary artery disease, Int J Cardiol (2013), http://dx.doi.org/10.1016/j.ijcard.2013.05.004

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therapy at the time of the trial, (c) the lower rate of complete revascularization among PCI patients, and (d) the lack of a stratification for the extent and complexity of CAD. The Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial [67] randomized diabetic patients with CAD to revascularization (CABG in the high-risk, PCI in the low-risk stratum) or medical treatment. At 5 years, there was no significant difference in the rates of death and major cardiovascular events (a composite of death, MI or stroke) between patients undergoing revascularization and those undergoing medical therapy. However, patients in the high-risk stratum who had been assigned to the CABG revascularization group experienced significantly fewer major cardiovascular events (22%) than patients assigned to OMT (30.5%, P = 0.01). In contrast, rates of cardiovascular events among patients in the low-risk stratum who underwent PCI did not differ significantly from those who were assigned to OMT. In a recent post-hoc analysis of 751 patients who were randomly assigned to early revascularization, with either CABG (n = 264) or PCI (n = 487), adjusted event-free survival was higher in patients with revascularization (HR 1.14; P b 0.01) [68]. These results were confirmed in the Future REvascularization Evaluation in patients with diabetes mellitus: Optimal management of Multivessel disease (FREEDOM) trial [69], where 1900 patients with diabetes and MVCAD were randomized to DES-PCI or CABG. The PCI group experienced a higher 5-year composite rate of death, MI or stroke (26.6%) as compared with CABG (18.7, P = 0.005). The benefit of CABG was driven by a reduced rate of both MI (P b 0.001) and death (P = 0.049), while stroke was more frequent in the CABG group. The high rate of adverse events observed in diabetic patients after PCI and the lack of benefit of PCI as compared with OMT are probably multifactorial but might be ascribed to the increased occurrence of restenosis and the accelerated disease progression occurring more frequently in PCI-treated arteries throughout the entire study duration [70], and therefore likely attributable to PCI-related vessel injury [71]. In a collaborative analysis of data from 10 randomized trials, longterm mortality was similar after CABG and PCI (performed with balloon in 6 and BMS in 4 trials) in most patient subgroups with MVCAD [72]; as compared with the cohort of patients who underwent PCI, mortality was significantly lower in the CABG group for patients ≥ 65 years (HR 0.82, P = 0.002) and with diabetes (HR 0.70, P = 0.014). The superior benefit of CABG was documented also among 2885 patients analyzed in a recent registry, where PCI showed a higher 5-year mortality (HR 1.8, P b 0.0001), MI (HR 3.3, P b 0.0001) and repeat revascularization (HR 4.5, P b 0.0001) [73]. The SYNTAX trial showed that diabetes increased MACCE rates among DES-PCI treated patients, but had little impact on results after CABG: in the diabetic subgroup, the 3-year MACCE rate (37.0%) was higher after DES-PCI as compared with CABG (22.9%, P = 0.002) [74]. One possible explanation of such results may be again the extent of the treatment. Specifically, among diabetic patients, the rate of angiographic complete revascularization was significantly lower among subjects treated with DES-PCI (47%) as compared with CABG (61%, P b 0.05). Moreover, as compared to PCI that is targeted to the treatment of the discrete lesion, CABG revascularizes the diseased vessel for its entire length, thus also being protective on subsequent atherosclerosis progression, that is extremely frequent in diabetic patients. The revascularization strategy for MVCAD diabetic patients should be discussed within a heart team consisting of cardiologists, cardiac surgeons, and anesthesiologists, trying to select the most effective and safe strategy to achieve an ischemia-guided complete revascularization. Based on the currently available evidence, the decision for CABG should be favored, with a lower threshold for diabetic as compared to non-diabetic individuals [75].

function significantly affects short- and long-term prognosis of patients with CAD [4]. Patients with CKD often present large number of comorbidities or a clustering of risk factors for vascular disease, such as arterial hypertension, erythropoietin deficiency, dyslipidemia, hypercalcemia and impaired hemostasis. The traditionally documented occurrence of frequent adverse events in such patients after angiography and either percutaneous or surgical revascularization produced a sort of diagnostic and therapeutic nihilism, dubbed “renalism” [76]. In a cohort of 57,284 elderly (≥65 years) subjects with MI, patients with CKD were less likely to receive coronary angiography and subsequent revascularization than those without CKD (P b 0.001 for both); however, after the correction for comorbidities, even the sole performance of coronary angiography was associated with a significant reduction in the risk of 1-year death (adjusted OR, 0.54; 95% CI 0.49–0.60) [76]. Despite the relative paucity of controlled data about patients with renal dysfunction, a “cautiously aggressive” approach seems effective: among 23,262 consecutive patients analyzed in the Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART) registry [77], an early invasive approach with a revascularization (PCI or CABG) within 14 days from admission for a NSTE-ACS was associated with an adjusted 36% lower 1-year mortality than medical therapy. The magnitude of benefit was consistent in normal-to-moderately impaired renal function groups (up to an estimated glomerular filtration rate – eGFR – of 30 mL/min/1.73 m2), declined with more severe renal dysfunction (eGFR 15–30 mL/min/1.73 m2), and was no longer evident in patients with kidney failure (eGFR b 15 mL/min/1.73 m2) and in those receiving dialysis. As to STEMI patients, the SWEDEHEART registry similarly documented that impaired renal function was independently associated with a less frequent use of antithrombotic drugs and revascularization in a logistic regression model [78]. According to the Kyoto model for predicting outcomes after revascularization strategy, in patients with mild or moderate CKD, (30 ≤ GFR b 60 mL/min/1.73 m2) CABG seems superior to PCI, particularly when diabetes is the underlying cause [79]. By contrast, in the subset of patients with severe CKD (GFR b 30 mL/min/1.73 m2) or end-stage renal disease, data supporting the clinical superiority of CABG are less convincing. Specifically, CABG is associated with a better long term event-free survival in such patients, but this approach is complicated by a higher in-hospital mortality rather than PCI [80]. In the DES era, a large single-center non-randomized observational study involving MVCAD patients with CKD showed similar rates of death, MI or cerebrovascular events with DES-PCI and CABG; however subjects with 3-vessel CAD receiving DES had a higher rate of 2-year repeat revascularization compared with those undergoing CABG. No analysis stratified for levels of CKD was available [81]. Among 275 propensity score-matched pairs of MVCAD patients submitted to complete or incomplete revascularization with PCI and followed for a median of 3.9 years, Chung et al. [82] recently documented an adjusted reduced risk of cardiac death or MI (HR 0.39, P = 0.03) associated with complete revascularization, and such benefit was more evident among diabetics (HR 0.27, P = 0.04), patients with LV dysfunction (HR 0.18, P = 0.01) and with an estimated GFR b 60 mL/min (HR 0.27, P = 0.05). Again, in MVCAD-CKD patients the “ad-hoc” treatment of either the culprit lesion in NSTE-ACS [83], or of the most critical lesion in the presence of chronic ischemia [84], followed by a staged PCI where necessary seems attractive to reduce the exposure to contrast medium. Even with such staged procedures it is however important to avoid 2 separate exposures to contrast within a short time frame [85]. 4.5. Impaired left ventricular function

4.4. Chronic kidney disease Cardiovascular disease is the leading cause of mortality in patients with severe chronic kidney disease (CKD), and an impaired renal

Differentiation between ischemic/viable myocardium and scar is vital in patients with LV dysfunction. A meta-regression analysis on 24 viability studies reporting patient survival documented a strong

Please cite this article as: Zimarino M, et al, The adequacy of myocardial revascularization in patients with multivessel coronary artery disease, Int J Cardiol (2013), http://dx.doi.org/10.1016/j.ijcard.2013.05.004

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Table 2 Major (>500 patients, ≥1-year follow-up) studies evaluating the prognostic implications of the adequacy of revascularization in subjects with multivessel coronary artery disease. Source of data Revascularization strategies

Main findings

Follow-up

1205

ARTS trial PCI–CABG

1 year

2002

1507

Kleisli [90]

2005

1034

Shishehbor [58]

2007

630

Tamburino [11]

2008

508

BARI trial CABG Single center CABG Propensity-matched Single center PCI Single center DES PCI

Hannan [91]

2009

11,294

Zapata [92]

2009

609

Rastan [17]

2009

8806

Sarno [93]

2010

1155

Kim [94]

2011

1919

KAMIR registry PCI

Wu [10]

2011

7606

Kim [23]

2011

1914

Song [95]

2011

873

Head [19]

2012

1766

Pair-matched patients New York State PCI registry Single center DES PCI–CABG Single center DES PCI SYNTAX trial PCI–CABG

CR was more frequently accomplished by CABG (84%) than by PCI (70.5%, P b 0.001). After PCI, patients with IR had a higher TVR than those submitted to CR. No differences in CABG patients. Death/MI was highest (32.9%, P = 0.03) when >1 anastomosis was constructed to any non-LAD system. Patients with CR had a higher survival (82.4%) than IR (52.6%, P b 0.001). In NSTE-ACS, multivessel PCI was associated with lower TVR rate (17%) than culprit-only (25%, P = 0.003) No differences for the composite end point of death or MI. As compared to IR, CR was associated with a reduced HR for cardiac death (0.37, P = 0.03), death or MI (0.34, P b 0.01) and 0.45 (P b 0.001) for TVR. Patients with CR showed a higher risk-adjusted survival (94.9%) than IR 93.8% (P = 0.01). In NSTE-ACS patients multivessel stenting was associated with lower rate of TVR (7.5% vs. 13.9%, P = 0.04). No difference in rates of death or MI. After LIMA to LAD CABG, similar survival was documented for CR (82.2%) and IR (80.9%, P = NS). CR was more frequently accomplished after CABG (84.1%) than PCI (61.2%, P b 0.05). Among PCI patients lower TVR rates after CR (83.1%) than after IR (75.4%, P = 0.03); no differences after CABG regardless CR. Among NSTE-ACS patients, as compared to culprit-only, multivessel PCI is associated with reduced cardiac mortality (3.5 vs. 6.4%, P = 0.009) and MI (0.6 vs. 2.1%). Among pair-matched patients, CR was associated with a higher survival (80.8%) as compared with IR (78.5%, P = 0.04).

Aggarwal [13]

2012

37,116

Chung [82]

2012

550

Propensity-matched Single center DES PCI

Schwartz [68]

2012

751

Generaux [61]

2012

2686

BARI 2D trial PCI–CABG ACUITY trial PCI

Girerd [20]

2012

1439

Propensity-matched CABG

Rosner [62]

2012

2954

ACUITY trial PCI

Author

Year

n

van den Brand [14]

2002

Vander Salm[16]

New York State PCI registry Single center PCI Single center CABG ARTS-II study DES PCI–CABG

Meta-analysis PCI

Angiographic CR and IR had similar death and a composite of death, MI and TVR rates. Compared to IR, CR was associated with a lower incidence of TVR (P = 0.01), but similar rates of death and MI. After PCI, patients with CR had reduced TVR rates (16.1%) as compared to IR (24.5%, P b 0.001), but not death and MI. No differences in outcomes were documented between CR and IR after CABG. As compared to IR, CR was associated to a lower risk of mortality (RR 0.82 P = 0.05), non-fatal MI (RR 0.67; P b 0.01) and subsequent CABG (RR 0.70; P = 0.02). As compared with IR, CR was associated with an adjusted reduced risk of death and MI (HR 0.51; P = 0.03). The benefit was more pronounced among patients with diabetes, reduced ejection fraction and renal dysfunction. Among diabetic patients, CR was associated with higher event-free survival (HR 1.14; P = 0.0018) as compared with IR. By multivariable analysis, the residual SYNTAX score was a strong independent predictor of all-cause mortality (HR = 1.05, P = 0.006), having a good discriminatory power for values >8. IR was independently associated with higher long-term mortality in patients b60 years (HR = 3.27, P = 0.02), not in patients 60–70 years and >70 years. IR in vessels with a DS ≥50% identified patients with a higher rate of MI (HR = 1.58, P b 0.001) and a trend toward increased risk of death (HR = 1.43, P = 0.13).

7 years 5 years 2.3 years

27 months

18 months 1 year

5 years 5 years

1 year

8 years

5 years 35 month 3 years

19–29 months

3.9 years

5.3 years 1 year

5.8 years

1 year

CABG = coronary artery bypass grafting; CR = complete revascularization; DES = drug-eluting stent; HR = hazard ratio; IR = incomplete revascularization; LAD = left anterior descending artery; LIMA = left internal mammary artery; PCI = percutaneous coronary interventions; MI = myocardial infarction; NSTE-ACS = non-ST elevation acute coronary syndrome; TVR = target vessel revascularization. See text for trials and registry acronyms.

association between myocardial viability on non-invasive testing and improved survival after revascularization in patients with chronic CAD and LV dysfunction, while the absence of viability was associated with no significant difference in outcomes, irrespective of the treatment strategy [86]. The prognosis of patients with chronic ischemic LV dysfunction and heart failure remains poor, despite advances in various therapeutic strategies. Current guidelines distinguish recommendations about revascularization in patients with impaired LV

function according to the predominance of angina or heart failure symptoms, reinforcing the concept that the choice between CABG and PCI should be based on a careful evaluation of the anatomy of coronary lesions, the expected completeness of revascularization, comorbidities, and associated significant valvular disease [4]. CABG is generally considered the preferred revascularization strategy, while PCI is judged acceptable only in the cases of suitable coronary anatomy and documented viable myocardium.

Please cite this article as: Zimarino M, et al, The adequacy of myocardial revascularization in patients with multivessel coronary artery disease, Int J Cardiol (2013), http://dx.doi.org/10.1016/j.ijcard.2013.05.004

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These assumptions about myocardial revascularization in patients with impaired LV function have been recently questioned by the Surgical Treatment IsChemic Heart failure (STICH) trial [87], in which medical therapy was compared with CABG in patients with severe (ejection fraction ≤ 35%) LV dysfunction. After nearly 5 years, mortality was similar in both groups, but patients undergoing surgical revascularization had a 19% lower risk of death from cardiovascular causes (P = 0.05) than patients in the medical therapy group. In a substudy of the STICH trial, the role of viability was also assessed [88]: here the presence of viable myocardium was associated with a greater likelihood of survival, but the assessment of myocardial viability itself did not identify patients with a differential survival benefit from CABG compared with medical therapy alone. On the other side, in the STICH 2 study [89], the adjunctive removal of non-viable myocardium with a surgical ventricular reconstruction did not provide any benefit beyond CABG in patients with ischemic cardiomyopathy symptoms: exercise tolerance, and rates of death or hospitalization for cardiac causes were similar regardless of LV reduction, after a median follow-up of 48 months. The role of ischemia in the outcome of this study was unclear and this is surely a major flaw in the trial design. 5. Conclusions The extent of myocardial revascularization is a major determinant of survival among MVCAD patients. Based on the available evidence (Table 2), revascularization with either CABG or PCI has similar benefits in terms of survival in patients with MVCAD, with a prognostic advantage for CABG in the presence of more extensive disease. There is growing evidence on the effectiveness of a functional evaluation in the choice of vessels and territories that should be targeted for both PCI and CABG, as the revascularization of non-viable myocardium or of a not relevant lesion gives all the disadvantages of an invasive procedure in terms of immediate risk, without any guarantee of longer-term benefit. Both PCI and CABG should always aim to be functionally complete. Diabetic patients and patients with more extensive disease have a reduced risk of death and/or MI when submitted to CABG, which more frequently attains complete revascularization. PCI is better suited in patients presenting with ACS and a suitable anatomy, where complete revascularization can be achieved through staged procedures that allow risk containment and functional evaluation of both myocardial viability/ ischemia and lesion relevance. The adequacy of revascularization should be a priority in the choice among PCI and CABG in patients with MVCAD and should guide physicians in a concerted multidisciplinary decision-making process taking into account the anatomy, function, extent of reversible ischemia and viability, comorbidities and, last but not least, the informed choices of the patient. References [1] Kushner FG, Hand M, Smith Jr SC, et al. 2009 focused updates: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update) a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2009;54:2205–41. [2] Wijns W, Kolh P. Appropriate myocardial revascularization: a joint viewpoint from an interventional cardiologist and a cardiac surgeon. Eur Heart J 2009;30:2182–5. [3] Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. Circulation 2011;124:e574–651. [4] Wijns W, Kolh P, Danchin N, et al. Guidelines on myocardial revascularization. Eur Heart J 2010;31:2501–55. [5] Ong AT, Serruys PW. Complete revascularization: coronary artery bypass graft surgery versus percutaneous coronary intervention. Circulation 2006;114:249–55. [6] Gossl M, Faxon DP, Bell MR, Holmes DR, Gersh BJ. Complete versus incomplete revascularization with coronary artery bypass graft or percutaneous intervention in stable

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Please cite this article as: Zimarino M, et al, The adequacy of myocardial revascularization in patients with multivessel coronary artery disease, Int J Cardiol (2013), http://dx.doi.org/10.1016/j.ijcard.2013.05.004

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Please cite this article as: Zimarino M, et al, The adequacy of myocardial revascularization in patients with multivessel coronary artery disease, Int J Cardiol (2013), http://dx.doi.org/10.1016/j.ijcard.2013.05.004